Her first husband was attorney Leo Panzirer, whom she divorced in 1952. Their only son was Jay (1940–1982), who had four children with his wife, Mimi. Leona was twice married to and divorced from her second husband, garment industry executive Joseph Lubin. After a brief period at a sewing factory, she joined a New York real estate firm, where she eventually became vice-president.

Roberts was a real estate salesperson in 1964 when Abe Hirschfeld hired her to sit in the lobby and sell at 925 Park Avenue in New York. She was a condominium broker in 1968 when she met and began her involvement with the then-married multi-millionaire real estate Entrepreneur Harry Helmsley. In 1970, she joined one of Helmsley's brokerage firms—Brown, Harris, Stevens—as a senior vice-president. At that time, she was already a millionaire in her own right. Helmsley divorced his wife of 33 years and married Roberts on April 8, 1972. Roberts's marriage to Helmsley may well have saved her career. Late in 1971, several of her tenants sued her for forcing the tenants of one of the apartments she managed to buy condominiums. They won, and she was forced not only to compensate the tenants but to give them three-year leases. Her real estate license was also suspended, so she focused on running Helmsley's growing hotel empire.

She was a chain smoker, consuming several packs a day. Helmsley would later claim that she appeared in billboard ads for Chesterfield cigarettes, but her claim remains unsubstantiated. She was linked romantically to St. Louis radio personality "Iggy" Strode in the 1980s.

On March 31, 1982, Helmsley's only child, Jay Panzirer, died of a heart attack resulting from arrhythmia. Her son's widow, who lived in a property that Helmsley owned, received an eviction notice shortly after his funeral. Helmsley successfully sued her son's estate for money and property that she claimed he had borrowed, and she was ultimately awarded $146,092.

In 1983, the Helmsleys bought Dunnellen Hall, a 21-room mansion in Greenwich, Connecticut, to use as a weekend retreat. The property cost $11 million, but the Helmsleys wanted to make it even more luxurious. The work included a $1 million dance floor, a silver clock and a mahogany card table.

The remodeling bills came to $8 million, which the Helmsleys were loath to pay. A group of contractors sued the Helmsleys for non-payment; the Helmsleys eventually paid off most of the debt owed to the contractors. In 1985, during those proceedings, the contractors revealed that most of their work was being illegally billed to the Helmsleys' hotels as Business expenses. The contractors sent a stack of the falsified invoices to the New York Post to prove that the Helmsleys were trying to avoid tax liabilities. The resulting Post story led to a federal Criminal investigation. Also, Jeremiah McCarthy, the Helmsleys' executive Engineer, alleged that Leona repeatedly demanded that he sign invoices to bill personal expenses to the Helmsley company and, when McCarthy declined to do so, Helmsley exploded with tyrannical outbursts, shouting, "You're not my fucking partner! You'll sign what I tell you to sign." In 1988, then United States Attorney Rudy Giuliani indicted the Helmsleys and two of their associates on several tax-related charges, as well as extortion.

In 1989, an unauthorized biography titled The Queen of Mean: The Unauthorized Biography of Leona Helmsley was published by Bantam Books (ISBN 978-0553285581). The 1990 TV movie Leona Helmsley: The Queen of Mean starred Suzanne Pleshette as Leona and Lloyd Bridges as Harry. Pleshette was nominated for an Emmy Award and a Golden Globe Award for the portrayal.

Helmsley's new Lawyer, retained to appeal the judgment, was Alan Dershowitz. Following the appeal, which resulted in a reduced sentence, she was ordered to report to prison on tax day, April 15, 1992. Her Federal Bureau of Prisons (BOP) Register number was 15113-054, and she was released from BOP custody on January 26, 1994, after serving 19 months.

Helmsley's later years were apparently spent in isolation, especially after Harry died in 1997. He left her his entire fortune, including the Helmsley hotels, the Helmsley Palace and the Empire State Building, estimated to be worth well in excess of $5 billion.

Although Helmsley had a reputation as the "Queen of Mean", some considered her generous in her charitable contributions after her prison term. After September 11, 2001, Helmsley donated $5 million to help the families of New York City firefighters and police. Other contributions included $25 million to New York–Presbyterian Hospital for medical research.

The will left her Maltese dog, Trouble, a $12 million trust fund. This sum was subsequently reduced to $2 million as excessive to fulfill its purpose. Her choice was branded 3rd in Fortune magazine's "101 Dumbest Moments in Business" of 2007.

In a judgment (published on June 16, 2008), Manhattan Surrogate Court Judge Renee Roth ruled that Helmsley was mentally unfit when she executed her will. Hence, the Court, amid settlement, reduced the $12 million trust fund for the pet Trouble to $2 million. Of the $10 million originally bequeathed to Trouble, $4 million was awarded to the Charitable Trust, and $6 million was awarded to Craig and Meegan Panzirer, who had been disinherited by the will. The ruling requires the Panzirers to keep silent about their dispute with their grandmother and deliver to the court any documents they have about her. It has been alleged that they were omitted from the will because they failed to name any of their children after Helmsley's late husband.

Leona Helmsley was born Lena Mindy Rosenthal in Marbletown, New York, to Polish Jewish immigrants, Ida (née Popkin), a homemaker, and Morris Rosenthal, a hatmaker. Her family moved to Brooklyn while she was still a girl, and moved six more times before settling in Manhattan. She dropped out of Abraham Lincoln High School to seek her fortune. She changed her name several times over a short period – from Lee Roberts, Mindy Roberts, and Leni Roberts – before finally going by Leona Mindy Roberts and having her surname legally changed to Roberts.

Trouble lived in Florida with Carl Lekic, the general manager of the Helmsley Sandcastle Hotel, with several death threats having been received. Lekic, Trouble's caretaker, stated that $2 million would pay for the dog's maintenance for more than 10 years—the annual $100,000 for full-time security, $8,000 for grooming and $1,200 for food. Lekic was paid a $60,000 annual guardianship fee." Trouble died at age twelve in December 2010, with the remainder of the funds reverted to the Leona M. and Harry B. Helmsley Charitable Trust. Although Helmsley's wishes were to have the dog interred with her in the mausoleum, New York state law prohibits interment of pets in human cemeteries and the dog was subsequently cremated.