In January 1905, Cole agreed to be the head football coach at the University of Virginia after graduating in the spring. He was hired at a salary of $1,800. Cole coached the Virginia team to a 5–4 record in 1905. After the season ended, Cole decided to leave coaching and begin his career as an attorney. After leaving Virginia at the end of the 1905 football season, Cole practiced law in Toledo, Ohio. In late August 1906, Cole was persuaded to return to Virginia to serve as football coach for another season. In 1906, his Virginia football team improved its record to 7–2.
In January 1907, Cole was hired by the University of Nebraska to take over as head coach of its football program. From 1907 to 1910, he coached at Nebraska and compiled a 25–8–3 record. Cole developed many strong players at Nebraska, and his Cornhuskers teams twice won the Missouri Valley Conference championship. In 1911, the Missouri Valley Conference adopted a new rule prohibiting "special coaching" and requiring that coaches must be full-time faculty members. Cole had purchased a ranch in Missoula, Montana that required his personal attention in the off-season. Unable to commit to a year-round position, Cole resigned as coach at Nebraska after the 1910 season in which he led Nebraska to a 7–1 record. Cole's last game as Nebraska's head football coach was a 119–0 win over the Haskell Indians, a point total that still ranks as the highest ever by a Cornhuskers team.
Cole's career record as the head coach at Marietta, Virginia, and Nebraska was 44–17–5. In his seven years of head coaching, he never had a losing record.