In 1963, Wexner was loaned $5,000 from his aunt to start The Limited (so named because the store focused on a limited amount of merchandise that turned over quickly and had a higher profit margin, unlike his parent's store).

The Limited opened its first store in the Kingsdale Shopping Center in Upper Arlington. Wexner's parents closed their store one year later and joined their son at The Limited. Wexner took Limited Brands public in 1969, listed as LTD on the NYSE. Wexner is the longest serving CEO of a Fortune 500 company. Wexner was ranked #11 on Harvard Business Review’s Top 100 Best Performing CEOs of 2015, and #34 in 2016.

In 1984, he established the Wexner Foundation whose goal is to strengthen the field of Jewish leadership. The foundation runs three major programs: the Wexner Heritage Program for North American Jewish volunteers; the Graduate Fellowship for students pursuing a master's degree in the rabbinate, cantorate, or Jewish studies; and an Israel Fellowship which funds Israeli public officials for a master's degree in public administration from Harvard University's John F. Kennedy School of Government.

Wexner was appointed to the board of trustees of Ohio State University and served from 1988 to 1997. In December 2005, Wexner was appointed to his second term and was elected chairman in 2009. Spring 2012 marked the end of Wexner's chairmanship and the announcement that he was stepping down later in the year, eight years before his appointment would have ended.

In 1989, Wexner and his mother Bella were the first to make a $1 million personal donation to the United Way. Both their names were inscribed in marble, and are on display in the lobby of the United Way Headquarters in Alexandria, Virginia.

Formerly of the Bexley area of Columbus, Ohio, Wexner now lives in New Albany, a community just north east of that city. He owns a 30-room, $47 million, Georgian inspired estate, on nearly 336 acres (4 km²) in Ohio built in 1990. The estate, was, for twenty years, the location of the Annual New Albany classic Invitational Grand Prix & Family Day benefiting The Center for Family Safety and Healing. Abigail Wexner announced the end of the event, citing the growing number of elite Equestrian competitions, in February 2018. The Classic consistently draws the top professional show jumping riders because of its well maintained and elaborate jumping course.

On January 23, 1993, Wexner, then 55 years of age, married Abigail S. Koppel, 31, a Lawyer, in a Jewish ceremony at their home in New Albany, Ohio. They have four children: Harry, Hannah, David, and Sarah.

At the time of its construction in 1997, Wexner's Limitless was the largest American-owned private yacht, measuring 315 feet and 8 inches (96.25 meters) long and 41 feet (12.50 meters) wide. Few authorized images exist, but photographs of the yacht's interior appear in an October 2016 retrospective of the career of the yacht's interior designer, François Catroux, written by David Netto and published by Rizzoli. The Limitless is one of the largest privately owned yachts in use.

On May 11, 2004, Wexner received the Woodrow Wilson Award for Corporate Citizenship at a dinner in Columbus, Ohio. The award was presented by the Woodrow Wilson International Center for Scholars of the Smithsonian Institution in Washington, DC. Wexner was honored because of his commitment to the public good.

President George W. Bush appointed Wexner to serve on the Honorary Delegation to accompany him to Jerusalem for the celebration of the 60th anniversary of the State of Israel in May 2008.

Wexner was inducted as an honorary member into the 104th Class of SPHINX Senior Class Honorary at The Ohio State University on May 7, 2010.

On February 16, 2011, Wexner pledged a donation of $100 million to Ohio State, which will be allocated to the University's academic Medical Center and James Cancer Hospital and Solove Research Institute, with additional gifts to the Wexner Center for the Arts and other areas. This latest gift is the largest in the University's history.

Wexner hosted a fundraiser for Mitt Romney in 2012. Wexner donated $250,000 to Restore Our Future, Romney's Super PAC. In 2015, Wexner donated $500,000 to the Right to Rise USA Super-Pac which supported the 2016 presidential campaign of Jeb Bush.

On December 11, 2013, Wexner was awarded the Women's Wear Daily Beauty Inc Visionary award.

As a pun on his name and his former residence in Bexley, the village of New Albany was known (unofficially) for some time as Wexley. Today, this Georgian-themed village inspires comparison to 18th century developments by wealthy aristocrats in England.