Waterfield entered the U.S. Army in 1943 and while in the service he was selected with the 42nd overall pick of the 1944 NFL Draft by the Cleveland Rams. He was discharged from the military due to a knee injury and returned to college and played for UCLA in 1944.
His rookie year in professional football was in 1945 and he started immediately. Waterfield was taken in quickly by fans, becoming the first ever rookie to win the league’s Most Valuable Player and unanimous All-NFL choice. He ended the season with a win in the NFL Championship game, where he threw touchdown passes of 37 and 44 yards as the Cleveland Rams beat the Washington Redskins 15-14. After the season, he signed a three-year contract for $20,000 per year, which made him the highest-paid player in pro football.
In 1946, the Rams moved to Los Angeles, California, where Waterfield became the star on the West Coast's first major professional franchise. He would later split time at quarterback with Norm Van Brocklin, who joined the team as a rookie in 1949. Behind this duo, Los Angeles played in three straight title games, 1949-1951. Runners-up in the first two, the Rams regained the league title in the 1951 championship game with a 24-17 win over the Cleveland Browns. It was the Rams' only league title during their 49 seasons in southern California (1946–94).
In a 1948 regular season game, the Rams were behind the champion-to-be Philadelphia Eagles 28-0. Waterfield managed to rally the team for a tie on four late touchdown passes. In the 1950 divisional playoffs, he was unable to practice due to a severe flu he had endured. However, he came off the bench anyway and threw three touchdown passes in a 24-14 win over the Chicago Bears.
In his first four seasons, he also played defense and intercepted a career total of 20 passes. As a place kicker, he had 315 successful PATs and 60 field goals, and as a punter, had a 42.4 yard average.
While an accomplished kicker and punter, Waterfield was best known for his ability to throw the deep ball. He led the NFL in passing in the 1946 and 1951 seasons, and ended his eight-year career with 814 completions, 11,849 yards and 97 touchdowns.
After several years in the film industry, Waterfield was hired as the Rams' head coach in 1960. After two seasons with four wins each, the third season in 1962 was even less successful and he resigned after the eighth game with just one win; his overall record was 9-24-1 (.289). He was later a team scout and a rancher near Van Nuys.
On April 24, 1943, he married actress Jane Russell, his sweetheart from Van Nuys High School who had subsequently gained fame as a popular pin-up girl. The couple eloped to Las Vegas shortly after Waterfield entered the military. They adopted three children during the 1950s. Russell divorced Waterfield in 1968. He married Janet Ann Green in 1970.