Holmes became head football coach at the University of Utah in 1900, and led the team to a record of 16–9–1; he was the first Utah coach to coach for multiple seasons. But his most enduring contribution at Utah may have been his composition of the lyrics to the school song "Utah Man." 
In 1904 Holmes became the first salaried head coach of the USC football team, and he compiled a 19–5–3 (.759) record over four seasons. USC's teams were called the Methodists before becoming the Trojans in 1912. In 1905, Holmes was the coach of the first USC team to play outside of Southern California. On November 4, playing a game at Stanford University, the Methodists were trampled 16–0 by the traditional West Coast powerhouse; it was also USC's first game ever against major college competition, an experiment which the team would not repeat until 1914. While USC and Stanford would not meet again until 1918 (Stanford dropped football for rugby during those years), this was the beginning of USC's oldest rivalry. But college football was going through a crisis period in which numerous players were dying in games every year, and many schools dropped the sport in favor of rugby for several seasons; the University of California switched from football to rugby from 1906 through 1914, and Stanford dropped football from 1906 through the end of World War I in 1918. Given its schedule featuring small colleges, high schools, and military and club teams, USC in that period had little need for a football coach with Holmes' credentials, and he departed in 1908; the university eventually switched to rugby from 1911 to 1913. Holmes' 1906 and 1907 teams had a combined record of 7–1–2, and outscored their opponents 218–20.
Holmes also coached the USC track team from 1905 to 1908, and was the first formal coach of the baseball team in 1908, posting a record of 17–2. He was succeeded as football coach by USC Law School graduate Bill Traeger.
In 1909 Holmes became football coach at the Academy of Idaho, where his teams had a record of 28–8 over six seasons, including perfect records of 4–0 and 6–0 in his first two years.