McMillon has worked for Walmart throughout his career. He took on his first role with the company as a teenager in 1984. He later became a buyer, then moved into management roles before becoming CEO in 2014.

When he was a teenager, McMillon began his first job with Walmart as a summer associate. He worked during the summer unloading trucks in a distribution center. After high school, McMillon attended University of Arkansas, where he graduated with a bachelor's degree in 1989.

The next year, as McMillon studied for a Master of Business Administration (MBA) from University of Tulsa, he called Walmart and told an executive he was interested in training to become a buyer when he completed his studies. Soon thereafter, McMillon rejoined Walmart as an assistant manager at a Tulsa, Oklahoma, store. After completing his MBA in 1991, McMillon moved to Walmart's Bentonville headquarters to join the buyer-training program. Originally in charge of buying fishing tackle, he later took on various roles as a buyer and a merchandiser, dealing in food, clothes, crafts and furnishings. He later worked as a general merchandise manager for Walmart's wholesale store division Sam's Club before taking an executive role at Walmart, overseeing toys, electronics and sporting goods, among other areas.

Walmart promoted McMillon to President and CEO of Sam's Club on August 4, 2005. Under McMillon, the wholesaler emphasized marketing to small Business customers. Additionally, McMillon incorporated what The Wall Street Journal called "treasure hunt" items that are limited-selection expensive premium items, such as Diamond necklaces and wine vacations, for sale next to cheap bulk goods in an attempt to compete with Costco.

Walmart officials moved McMillon from his role at Sam's Club to lead Walmart's international division in February 2009, replacing mike Duke, who was promoted to CEO of Wal-Mart Stores, Inc. Under McMillon, Walmart International focused on improving in existing markets, such as Canada, China, United Kingdom and the Americas. One area of particular importance to McMillon was integrating Walmart's "everyday low prices" model to these international markets. Under McMillon, the international division acquired a majority stake in South Africa's Massmart Holdings Ltd. for US$2.4 billion.

Walmart announced on November 25, 2013, that McMillon would immediately join the company's board of Directors, and would replace mike Duke as Walmart CEO effective on February 1, 2014, becoming the company's fifth-ever chief executive.

Forbes named McMillon to its World's Most Powerful People list in 2014, 2015 and 2016 where he ranked No. 29, No. 32, No. 27 respectively. ExecRank ranked McMillon No. 4 on its 2015 list of top CEOs for large companies.

In June 2015, McMillon said the company would stop selling Confederate flag merchandise following the shooting of nine black churchgoers in Charleston, South Carolina. McMillon altered Walmart's gun sales. He told CNNMoney in an interview that Walmart's selection of firearms should be geared towards Hunters and Sports shooters. In August 2015, the company ceased sales of military-style semiautomatic weapons.

In December 2016, McMillon joined a Business forum assembled by then president-elect Donald Trump to provide strategic and policy advice on economic issues. In August 2017, McMillon wrote a rebuke of President Trump's response to the violent protests Charlottesville, Virginia in an email to all employees and on the internal company website that is viewable by the public. The statement said the President, "missed a critical opportunity to help bring our country together". A company spokesman said McMillon would continue to serve on a presidential advisory council on economic development.