Lachky said that he was moving on to "explore new challenges" and denied that the decision was related to InBev's $52bn (£36bn) purchase of Anheuser-Busch, which took place four months ago.
David Peacock, president of Anheuser-Busch, said that Lachky will not be replaced as the company is taking a more "decentralised" approach to creative development in the future.
Lachky, who joined the company 20 years ago as senior brand manager for Bud Light, has worked on some of the company's most celebrated ads and icons including 'Whassup?', Real men of genius', the 'Bud-weis-er' frogs and the Budweiser Clydesdale horses.
Lachky also spearheaded the development of Anheusers-Busch's Super Bowl ads, which dominated post-game polls for virtually his entire time at the company.
Lachky said that he is not retiring but has not given details about his future.
His departure is not likely to go down well with Anheuser-Busch's roster of creative agencies. Lachky was most closely tied to Omnicom Group's DDB, which has been the brewer's lead agency since 1994.
Anheuser-Busch also works with Havas's Euro RSCG and Omnicom's Goodby, Silverstein & Partners.
Lachky is the second big marketer to leave the company following the sale to InBev.
Tony Ponturo, vice president of global media and sports marketing, announced he was retiring at the end of last year.