After serving in the United States Navy in World War II, Kauffman worked as a pharmaceutical salesman until 1950, when he formed Marion Laboratories in 1950 with a $5,000 investment, operating it initially out of the basement of his home. He reportedly chose to use his middle name rather than his last name in order to not appear to be a one-man operation.
Kauffman founded the Ewing Marion Kauffman Foundation in the mid-1960s to provide cash grants to encourage entrepreneurship across America and improve education for children and youth, mostly in and around the Kansas City metropolitan area.
At the encouragement of his wife, Muriel, Kauffman bought the Kansas City Royals as an expansion franchise in 1968 and owned the team until his death in 1993. During his ownership the team won six division titles, two league championships, and one World Series. In his will, Kauffman stipulated that the Royals must retain 50% local ownership, and that the proceeds of the sale of the team would go to Kansas City area charities. A month before his death, Royals Stadium was renamed Kauffman Stadium in his honor.