After serving in the United States Navy during World War II, he left acting, but was persuaded by director William Wellman in the 1950s to resume his film career.

[4] Hopper's film roles included Stagecoach (1939), The Return of Dr. X (1939), Over the Goal (1939), Knute Rockne, All American (1940), The Maltese Falcon (1941) and Yankee Doodle Dandy (1942).

"[12] Hopper served with the United States Navy during World War II, as a volunteer with the Office of Strategic Services[7][13] and as a member of the newly created Underwater Demolition Team.

[15] "I didn't even think about acting much until a friend, director Bill Wellman, asked me to do a part in The High and the Mighty," Hopper recalled.

[12] In 1953, director William Wellman persuaded Hopper to resume his movie career with his 1954 film, The High and the Mighty,[16] opposite Jan Sterling.

[4] Hopper was cast to star opposite Claire Trevor in the live television drama "No Sad Songs for Me",[8]: 61  broadcast April 14, 1955, on NBC's Lux Video Theatre.

[4] In 1956 Hopper guest-starred again on television during the first season of the Western series Gunsmoke, portraying an outlaw initially supported by townsfolk in an episode titled "Robin Hood".

Some of Hopper's other television guest appearances include The Joseph Cotten Show: On Trial, Fury, Studio 57, and The Millionaire.

Hopper is best known for his principal role as the private investigator Paul Drake on CBS's courtroom television series Perry Mason (1957–66).

Executive producer Gail Patrick Jackson recalled, "When Bill Hopper came in to read for Paul Drake he blurted out, 'You hate my mother.'

"[20] Wrote Brian Kelleher and Diana Merrill in their chronicle of the television series:[8]: 61 As Paul Drake, William Hopper was called on to be the most versatile of the principals in the Perry Mason cast.

[8]: 65 Hopper continued to work in summer stock and to make movie appearances during his years on Perry Mason; however, after the series was cancelled in 1966, he declined other television offers.

[8]: 66 [21] In 1959, Hopper was nominated as Best Supporting Actor (Continuing Character) in a Dramatic Series at the 11th Primetime Emmy Awards for his performance as Paul Drake.

[28] Hopper entered Desert Hospital in Palm Springs, California,[14] on February 14, 1970, after suffering a stroke.