Simmons was born in Golden, Wood County, Texas, the son of Reuben Leon (1894 -1954) and Fairess Clark Simmons (1903-1990). His parents were Baptists and both worked as teachers. His Father later became a school superintendent. Simmons has BA (1951) and MA (1952) degrees in economics from the University of Texas at Austin. Simmons holds a Phi Beta Kappa key.

After completing graduate school in 1952, Simmons worked for the U.S. government as a bank examiner, then for a Dallas-based bank, Republic National Bank.

Annette and Harold Simmons have been underwriters for 28 consecutive years to the Dallas Crystal Charity Ball Fashion Show and Luncheon. The Crystal Charity Ball has distributed more than $82 million to children's charities since 1953.

In 1960, using $5,000 of his savings, and a $95,000 loan, he bought a small drugstore, University Pharmacy on Hillcrest Avenue, across from the campus of Southern Methodist University. Before Simmons owned it, University Pharmacy was the site of a racially charged sit-in in January 1961, when its owner C.K. Bright sprayed insecticide over and around 60 students, only two of whom were black seminary students. Simmons purchased the store and parlayed it into a chain of 100 stores, which in 1973 he sold for more than $50 million, to Eckerd Corporation. This launched his career as an investor, when he used the proceeds of that sale to begin speculation in the financial services industry. By 1974, he had been indicted for and acquitted of wire and mail fraud, and involved in a pension-related lawsuit brought against him by the United Auto Workers.

In 1973, Simmons was a significant contributor to the Dallas Civic Opera.

Simmons conducted a widely publicized but unsuccessful takeover attempt on the Lockheed Corporation, after having gradually acquired almost 20 per cent of its stock. Lockheed was attractive to Simmons because one of its primary Investors was the California Public Employees' Retirement System (CalPERS), the pension fund of the state of California. At the time, the New York Times said, "Much of Mr. Simmons's interest in Lockheed is believed to stem from its pension plan, which is over financed by more than $1.4 billion. Analysts said he might want to liquidate the plan and pay out the excess funds to shareholders, including himself." Citing the "mismanagement" of its chairman, Daniel M. Tellep, Simmons stated a wish to replace its board with a slate of his own choosing, since he was the largest investor. His board nominations included former Texas Senator John Tower, the onetime chairman of the Armed Services Committee, and Admiral Elmo Zumwalt Jr., a former Chief of Naval Operations. Simmons had first begun accumulating Lockheed stock in early 1989 when deep Pentagon cuts to the defense budget had driven down prices of military contractor stocks, and analysts had not believed he would attempt the takeover since he was also at the time pursuing control of Georgia Gulf.

Between 1993 and 1997, Simmons and family members and Contran gave more than $315,000 to Republican candidates, according to FEC records.

In August 1997, President Bill Clinton used a line-item veto to draw attention to the type of "special benefits" that Investors such as Simmons employ to avoid paying capital gains taxes since the early 1980s. Simmons had formed the "Snake River Sugar Cooperative" of 2,000 beet farmers and Classified it as a joint-venture, shared ownership co-op, to purchase his Amalgamated Sugar Company, for $260 million. At the time, Charles Schumer, serving as a Representative from New York, wrote a letter to Clinton stating that the measure before him for consideration would benefit Simmons with a $104 million tax deferral. Simmons stated at the time that his tax deferral was only $80 million.

Charles Cameron Sprague Community Service Award Annette G. Strauss Humanitarian Award 2002 Angel of Freedom Award,(Harold Simmons Foundation) Human Rights Initiative

During the 2004 presidential campaign Simmons made a $4 million donation to the group Swift Vets and POWs for Truth. He also donated $100,000 to George W. Bush's January 2005 inaugural ball.

Simmons donated money to help fund the Hobby-Eberly Telescope Dark Energy Experiment at the University of Texas. He has previously given to UT athletic programs and the McCombs School of Business. By 2005, total donations from his family and foundation to the UT Southwestern Medical Center at Dallas exceeded $70 million.

Since mid 2006, Simmons has given funds to a chronic kidney disease research team led by Dr. Kamyar Kalantar-Zadeh to examine predictors of longevity in chronic kidney disease. Subsequently, the “Harold Simmons Center for Chronic Disease Research and Epidemiology” was created, first in “Los Angeles Biomedical Research Institute” at “Harbor-UCLA Medical Center” then in UC Irvine Medical Center at University of California, Irvine School of Medicine, in Orange, CA, which has published a large number of scientific reports and articles.

In 2007, Harold and Annette Simmons announced a $20 million gift to Southern Methodist University to provide an endowment for the university's School of Education and Human Development. The gift allocated $10 million for construction of a new facility, to be named the Annette Caldwell Simmons Building; $5 million for graduate student fellowships; and $5 million for faculty support and an endowed deanship.

In 2008 the Harold Simmons Foundation made a donation of $5 million to the Dallas Zoo, the largest single private contribution in the zoo's 120-year history.

The Harold Simmons Foundation made a gift to the Legal Hospice of Texas, a nonprofit law firm providing compassionate legal services at no charge to low-income individuals who are terminally ill, in 2010 and 2012.

Simmons's company, Contran Corporation, donated $1 million to Make Us Great Again, a super PAC supporting Rick Perry's 2012 presidential candidacy. That donation was the single largest received by the PAC in the fourth quarter of 2011. According to a CBS article, Contran also was the largest donor to American Crossroads, giving $2 million to the conservative super PAC co-founded by Karl Rove. Later data from Opensecrets.org shows Contran contributions of $5 million in Nov 2011, $5 million in Jan 2012, and $1 million in April 2012 to American Crossroads. Simmons also donated $100,000 directly to another Perry super PAC, the Restoring Prosperity Fund, before donating $5 million to American Crossroads in addition to Contran's donation. He has also contributed to Restore our Future, a super PAC supporting Mitt Romney. His contributions in support of Romney totaled $16.5 million, making him the year's third-largest Republican donor, behind Sheldon Adelson and Bob J. Perry.

Two of Harold Simmons’ companies – Southwest Louisiana Land which he owns and Dixie Rice Agricultural Corp in which he was a major investor – were each $1 million donors to the American Crossroads, a 527 organization working to elect primarily Republican legislators during the 2010 midterm elections.