Kelley grew up on a farm that included tobacco, and his early business ventures were a response to changes in the tobacco industry. Because of declining production in the 1980s, many old warehouses in Kentucky stood vacant. He started buying these warehouses, converting them to other uses, and then leasing them out. This interest evolved into manufacturing. In 1991, he founded Commonwealth Brands, a tobacco company that manufactured low-cost cigarettes, headquartered in Bowling Green, Kentucky. The company was later sold in 2001 to Houchens Industries for US$1 billion. Kelley has never smoked, and he said in 2012, “I’ve never defended [smoking]. Hopefully it will be phased out of society.”

In May 2012, Kelley became the operator of the historic Calumet Farm in Lexington. He was already involved in Thoroughbred breeding and racing operations. He was formerly the largest shareholder and a board member of Churchill Downs. In May 2013, his colt Oxbow won the Preakness Stakes.

In March 2013, the commercial arm of the BBC, BBCW, announced the sale of Lonely Planet to Kelly’s NC2 Media. Lonely Planet is the world’s most successful guidebook publisher, having printed over 100 million guidebooks, in addition to magazines, digital content, and other travel services.

In January, 2020, Kelley put up for sale many of his West Texas ranches, offering roughly 500,000 acres with a listing price of $404 million.