Perelman is the owner of "Près Choisis" (now called "The Creeks"), a 40-room Mediterranean-style villa on Georgica Pond in East Hampton, Long Island. It was built in 1899 by the artists Adele and Albert Herter.

Perelman was born in Greensboro, North Carolina on January 1, 1943, the son of Ruth (née Caplan) and Raymond G. Perelman. He was raised in a Jewish family. He managed with family members the American Paper Products Corporation. Raymond eventually left the company and bought Belmont Iron Works, a manufacturer of structural steel.

Perelman first attended Villanova University's School of Business (Fall, 1960), then attended the Wharton School of the University of Pennsylvania where he followed in his father's footsteps and majored in Business. He graduated in 1964 and completed his master's in 1966.

Perelman's first major Business deal took place in 1961 during his Freshman year at the Wharton School of the University of Pennsylvania. He and his father bought the Esslinger Brewery for $800,000, then sold it three years later for a $1 million profit.

Perelman met his first wife, Faith Golding, in 1965 while on a cruise to Israel. As the heir to a fortune made in real estate and banking, Faith Golding controlled a personal fortune of around $100 million at the time of their marriage. They adopted three children named Steven, Josh, and Hope, and Faith gave birth to a fourth child named Debra. Their marriage lasted until 1984 when Faith discovered Perelman was having an affair with a local florist after a bill for a Bulgari bracelet was sent to their home instead of Perelman's office. Faith threatened to scuttle Perelman's attempt to take MacAndrews & Forbes private in 1983 by staking a claim to a third of it due to a bank loan in her name. She further declared that Perelman defrauded the owners of the First Sterling Corporation (i.e. her) by buying thousands of dollars of gifts for the florist with the company's money, and made a very public spectacle of the divorce. Perelman responded by hiring Roy Cohn and flatly denying all of the allegations. The pair quickly settled the divorce with an estimated payout to Faith in excess of $8 million.

He orchestrated the purchase of Cohen-Hatfield Jewelers in 1978, his first deal as an independent investor free of his father's influence. He recognized the enormous value of Hatfield's mismanaged jewelry cache and bought control of the company with a $1.9 million loan from his wife, Faith Golding. Within a year, Perelman had sold all of the company's Retail locations and reduced the company to its lucrative wholesale jewelry division, earning him $15 million.

In the late 1980s, Perelman was accused of engaging in greenmail. "Greenmail" occurs when someone buys a large block of a company's stock and threatens to take over the company unless he is paid a substantial premium over his purchase price. In the case of someone with a reputation as a corporate raider, the mere act of buying up shares could send a company into a panic and Investors into a buying frenzy. Perelman insists he seriously intended to buy every corporation he bought into.

Also in 1983, MacAndrews had acquired Technicolor Inc. Despite the bond debt, in 1984, MacAndrews & Forbes purchased Consolidated Cigar Holdings Ltd. from Gulf & Western Industries, in addition to Video Corporation of America. The Technicolor Inc. divisions were sold off and, in 1988, its core Business was sold to Carlton Communications for 6.5 times the purchase price. Using the proceeds from the Technicolor division sell off, MacAndrews & Forbes purchased a 20 percent stake in Compact Video Inc., a television and film syndication company. Ronald Perelman's controlling buyout of Compact Video was in 1986.

Perelman met his second wife, Claudia Cohen, in 1984 at Le Cirque. They had one daughter together, Samantha, in 1990. In August 1993, Ron filed for divorce. Claudia left the marriage with well over $80 million. In 2007, Claudia died after a secret seven-year battle with ovarian cancer. Perelman revealed during his speech at her funeral that he'd known about her cancer from the beginning and privately commissioned a vaccine as a part of his efforts to cure her. In March 2008, Perelman decided to change the name of Logan Hall, located at the University of Pennsylvania, to Cohen Hall, after his late ex-wife. He donated $20 million to the University to remodel what is now Perelman Quadrangle and as part of his donation, he had the option to change the name of Logan Hall. His decision to rename Logan Hall dismayed some Penn faculty, alumni, and students.

Perelman hired Fred Tepperman as his CFO after Tepperman left Warner Communications in 1985. Starting with Pantry Pride, Tepperman worked on every single Business deal Perelman orchestrated throughout Tepperman's seven-year stint at MacAndrews & Forbes. Tepperman's tenure came to an abrupt end just after Christmas in 1991 when Perelman fired him for being derelict in his duties. Tepperman had been distracted, he claimed, by caring for his Alzheimer's-afflicted wife of 30 years. A clause in Tepperman's contract entitled him to a large portion of his salary and benefits in the event of an injury that prevented him from being able to work; Tepperman claimed he had suffered such an injury, albeit psychologically, as a result of the effect his wife's condition had on him. His demands totaled $30 million. That number stems partially from Tepperman's salary, which started at $275,000 and rose to $1.2 million in 1990 and partially from his large benefits package. Perelman was quick to file a countersuit for fraud, claiming that Tepperman had sneakily changed the company's retirement plan in such a way that Tepperman would personally gain millions of dollars. It took over three years for the case to make it to court. The case ended with a sealed settlement.

Another accusation of greenmailing levied against him was the best-known and stemmed from his attempt to purchase Gillette in November 1986. Perelman opened negotiations with a bid of $4.12 billion. Gillette responded with an unsuccessful lawsuit and public insinuations of insider trading. Perelman accumulated 13.8% of Gillette before he made what he would later call the worst decision he ever made and sold his stake to Gillette later that month for a $34 million profit. Gillette had put word out that Ralston Purina had agreed to buy a 20% block of stock, making any attempt by Perelman to buy Gillette much more difficult. Perelman decided to sell his share to Ralston Purina, but before he did so Gillette's executives called him up, asking if he'd sell his shares to them and they'd sell the shares to Ralston Purina. He sold his shares to Gillette and Ralston backed out of the deal.

In 1989, Perelman acquired New World Entertainment, with David Charnay's Four Star Television becoming a unit of Ronald Perelman's Compact Video, later that year. Ownership of Compact Video Inc. was increased to 40% in 1989 after the buyout of Four Star International. After Compact shut down, its remaining assets, including Four Star, were folded into MacAndrews and Forbes Incorporated. In 1989, Perelman also acquired New World Entertainment with Four Star becoming a division of New World as part of the transaction. Four Star International was purchased through a golden parachute deal that was negotiated with David Charnay by Ronald Perelman after Charnay was notified of stock purchases made by Perelman in 1989. By the end of 1989, MacAndrews refinanced the Holding companies' Jun K bonds for standard bank loans. The bulk of New World's film and home video holdings were sold in January 1990 to Trans-Atlantic Pictures, a newly formed production company founded by a consortium of former New World executives.

In 1993, the Entertainment Industry Foundation (EIF) Revlon Run/Walk For Women was created through the combined efforts of Perelman, Lily Tartikoff, co-founder of the Revlon/UCLA Women's Cancer Research Program, and the EIF. The New York and Los Angeles Run/Walk events together have distributed over $50 million for women's cancer research, counseling and outreach programs nationwide.

MacAndrews & Forbes established the Revlon/UCLA Women's Cancer Research Program in 1994 for research into the causes and treatment of breast and ovarian cancer. The company also founded the Ronald O. Perelman Department of Dermatology at NYU Medical Center. Over the years, MacAndrews & Forbes has also provided significant support for such organizations as the National Breast Cancer Coalition Fund, Carnegie Hall, the Solomon R. Guggenheim Museum, Memorial Sloan-Kettering Hospital and Perelman's alma mater, The University of Pennsylvania.

Patricia Duff was Perelman's third wife. The pair first met in a Paris hotel lobby when both were still married: Perelman to Cohen, and Duff to Mike Medavoy. After Duff divorced Medavoy, Duff converted to Judaism and married Perelman, on January 25, 1995. She gave birth to his fourth daughter, Caleigh Sophia, before the wedding took place. When the marriage between Duff and Perelman disintegrated in 1996, custody over Caleigh became a major issue. Both Perelman and Duff wanted full custody and their prenuptial agreement did not address the subject of child support. Initially private, the divorce proceedings were opened to the public at the request of Duff. Neither party emerged with their reputations unscathed. The court Psychiatrist found Duff to be paranoid and narcissistic and Perelman to have serious anger management issues, Perelman caught a great deal of flak for testifying that it cost about $3 a day to feed his daughter, and both sides alleged physical abuse by the other party. The judge's sealed decision means the public will never know the exact results of the case, but it's known that neither party actually won. Perelman is Caleigh's legal guardian, but Patricia has extensive visitation rights.

Perelman stumbled into the Lewinsky scandal. In early 1998, Vernon Jordan recommended Monica Lewinsky to Perelman as a potential employee, pitching her as a very smart young woman. While Jordan was on the Revlon board of Directors, Jordan rarely spoke to Perelman and had never before recommended anyone to him. Jordan indicated he'd already talked about Lewinsky with MacAndrews & Forbes Holdings vice President, Jaymie Durnan. Durnan told Perelman that he had determined there was no position available for Lewinsky at Perelman's company, but that he had forwarded Lewinsky's resume to Revlon. Perelman claims to have been as surprised as anyone when he found out about the Lewinsky–Clinton connection later that month. He found that Revlon had already made a job offer which was quickly withdrawn, but it was too late; Revlon and Perelman were all over the scandal.

Perelman met his fourth wife, Actress Ellen Barkin, at a Vanity Fair Oscar after-party in 1999. After slightly more than a year of courtship, the two married in June 2000. All accounts indicate their five-year marriage was a stormy one. Much of the friction arose due to Barkin's acting career and her attendant travel schedule. Perelman filed and obtained a divorce in early 2006. The press soundly mocked Perelman for his actions, the speed and timing of which suggested his real motivation was to avoid a clause in his prenuptial that would raise the amount in alimony he owed Barkin if he waited a few days longer. Depending on the source used, Barkin's yearly alimony ranges from $2 million to $3 million and the total payout ranged from $20 million to $65 million. In late 2007, the pair exchanged lawsuits. Part of the divorce settlement required Perelman to invest several million dollars in a film production company Barkin and her brother George (an aspiring screenwriter) had started. Perelman made only one of the payments, claiming that there was no evidence the two were actually producing films. Barkin sued for her money while Perelman counter-sued, alleging Barkin and her brother had looted the film company for themselves.

In April 2001, M&F Worldwide bought Perelman's 83% stake in Panavision for $128 million. This would be unremarkable except that Perelman controlled M&F Worldwide and the price paid for his stake was four times market value. At the time, M&F Worldwide was a healthy company with an excellent balance sheet while Panavision was bleeding red ink. M&F Worldwide's other shareholders cried foul, alleging the only person who stood to benefit from the deal was Perelman and took their complaints to the courts. Perelman insisted the deal was an excellent one and in the best interest of the shareholders because Panavision was well-positioned to profit from the move to digital cinematography. The share price tumbled from six to three after the deal and reflected M&F Worldwide shareholders' lack of confidence. Perelman tried to pacify M&F Worldwide's shareholders with a $15 million settlement, but the judge rejected it as grossly inadequate. Ultimately, Perelman agreed to undo the deal.

On February 17, 2005, Perelman filed a lawsuit against Morgan Stanley. Two facts were at issue. Did Morgan Stanley know about the problems with Sunbeam and was Perelman misled? During the discovery phase, the judge became exasperated with what she perceived as deliberate stonewalling on the part of Morgan Stanley and ordered the jury to assume Morgan Stanley deliberately and knowingly defrauded Perelman. Hobbled, Morgan Stanley had no choice but to argue that Perelman was too savvy an investor to have fallen for their transparent tricks. After a five-week trial, the jury deliberated for two days, found in favor of Perelman, and awarded him $1.45 billion. The damages stung particularly because Morgan Stanley passed up Perelman's offer to settle the case for $20 million. Morgan Stanley maintained that the court case was improperly decided, citing the judge's decision to use Florida law over New York law and her decision to order the jury to consider Morgan Stanley guilty before the trial began. In 2007, the courts of appeal reversed the judgement. The judges declared Perelman hadn't provided any evidence showing he'd suffered any actual damage as a result of Morgan Stanley's actions. Perelman appealed, but found himself shot down by the Florida Supreme Court who dismissed it in a 5–0 decision. Undeterred even after that setback, Perelman went back to the trial court and asked for the case to be reopened because the hiding of email evidence was "a classic Example of fraud on the court". The trial court rejected his arguments, but as of January 2009, he is beseeching Florida's 4th Circuit to reopen the case.

Perelman began dating Psychiatrist Dr. Anna Chapman, in mid-2006. In August 2010, they announced they are expecting a baby—her first, his seventh—via a surrogate. In October 2010, they were married. Chapman is a convert to Judaism. In late November 2010, the couple celebrated the birth of their son, Oscar. The couple later had a second child in May 2012.

In 2008, the Chronicle of Philanthropy listed Perelman as the 26th largest donor in the U.S. That year, Perelman donated $63.5 million to causes including, but not limited to: Weill Medical College of Cornell University, Stand Up to Cancer (SU2C), World Trade Center Memorial Fund and Ford's Theatre.

Perelman has been married five times. He married Sterling Bank heiress Faith Golding in 1965 and they divorced in 1984. His marriage to gossip columnist Claudia Cohen lasted from 1985 to 1994. He wed socialite Patricia Duff in 1995 and divorced in 1996. He was married to Actress Ellen Barkin from 2000 to 2006. On October 13, 2010, Perelman married Dr. Anna Chapman, a Harvard-educated Psychiatrist.

In 2011, Perelman's parents, Raymond and Ruth, donated $225 million to the University of Pennsylvania School of Medicine, the largest single donation to that university in its history, changing the school's name to the Perelman School of Medicine at the University of Pennsylvania. His mother, Ruth, died on July 31, 2011, at age 90 in Philadelphia.

In May 2013, Perelman donated $100 million to the Columbia Business School, the graduate Business school of Columbia University. The gift will be used to support the construction of new facilities in Manhattanville, including the Ronald O. Perelman Center for Business Innovation.

In 2015, Perelman donated $500,000 each to Super PACs supporting the presidential candidacies of Lindsey Graham and Jeb Bush.

In 2016, Perelman donated $75 million to revive plans to build a performing arts center at the World Trade Center site. Brooklyn native Barbra Streisand is serving as Chairwoman of the Ronald O. Perelman Performing Arts Center. In September 2016, the design for the Ronald O. Perelman Performing Arts Center were unveiled.