A native of Charlestown, Massachusetts, O'Donnell attended the Boston Latin School before enrolling at the College of Holy Cross in 1904. He played four years for the Holy Cross Crusaders football team. He was a tackle in the 1904 and 1905 seasons, and end in 1906, and a fullback in 1907. In the final game of the 1906 season, played at the Polo Grounds, O'Donnell scored both of Holy Cross's touchdowns in 15–6 win over Fordham. He was selected by his teammates as captain of the 1907 team. His final game for Holy Cross was a 34–0 loss to Fordham. Despite the one-sided game, The New York Times singled out "O'Donnell's Pretty Play" as the feature of the contest. The Times wrote:
Again and again by the sheer force of his phenomenal running O'Donnell took the ball through the Fordham line and gained a dozen first downs. In fact, not once during the whole progress of the game was the remarkable back stopped for a loss, but, unsupported as he was, the herculean task of beating a well-drilled eleven was too much for him.... Several stretches of thirty yards were made by his rushing, but eventually Holy Cross was forced to kick, and their advances ended there.
O'Donnell graduated from Holy Cross in 1908 and began his coaching career at Somerville High School, Somerville, Massachusetts. In September 1909, he was hired as the football coach at Everett High School, Everett, Massachusetts. He served as the head coach at Everett for seven years from 1909 to 1915. His teams won championships in five of the seven seasons that O'Donnell was the coach. In 13 games, O'Donnell's 1914 Everett team went 13–0 and outscored opponents 600 to 0. In the national championship of high school football, Everett, the best team in the East, was matched against Oak Park High School from Illinois, the best team in the West. Everett defeated Oak Park 80 to 0. The Boston Evening Transcript wrote at the time, "Since Cleo O'Donnell took charge of the Suburban League school's athletics, he has had remarkable success, but this year's team is his masterpiece." Seventy years later, Sports Illustrated published a feature story on the 1914 Everett team, declaring it possibly the greatest high school football team of all time. O'Donnell became known for the stylish suits he wore on the sidelines at Everett and developed a reputation as "a demanding perfectionist." As the coach at Everett, O'Donnell compiled a record of 68–8–6, and through one stretch between 1913 and 1915 his team shut out all opponents in 25 consecutive games. In March 1916, O'Donnell was hired as the head football coach at Purdue University. In two seasons as the coach at Purdue, his teams lost eight out of nine games against Western Conference opponents and compiled an overall record of 5–8–1. In August 1919, O'Donnell returned his alma mater as the head football coach of the Holy Cross Crusaders. He remained the head coach at Holy Cross from 1919 through 1929. In his 11 years at Holy Cross, his teams posted a combined record of 69–27–6. He never had a losing season at Holy Cross, and his 1923 team outscored opponents 272 to 29. In early 1930, O'Donnell stepped down as head football coach at Holy Cross, but remained at the school as athletic director until December 1933. In April 1935, O'Donnell was hired as the head football coach and athletic director at Saint Anselm College in Goffstown, New Hampshire. O'Donnell was the head coach at Saint Anselm for six seasons from 1935 to 1940. In January 1941, O'Donnell resigned his position at Saint Anselm. In 1945, O'Donnell was hired as the high school football coach at Fitchburg, Massachusetts. In February 1953, O'Donnell collapsed and died suddenly while attending a testimonial dinner for his former pupil, Harry McMahon, at Southbridge, Massachusetts. His son Kenneth O'Donnell was an aide to President John F Kennedy, and his grandson Kevin M. O'Donnell is the co-founder of Earthlink. O'Donnell was inducted into the Holy Cross Athletics Hall of Fame in 1962. He was also inducted into Saint Anselm College's Anselmian Athletic Club Hall of Fame in 1985.
