Selected in the 15th round (135th overall) of the 1942 NFL Draft out of Utah by the Detroit Lions, Mac Speedie chose to pause his professional football journey to serve in the U.S. Army during World War II. After returning, he eagerly tried out for Paul Brown's inaugural 1946 Cleveland Browns in the emerging All-America Football Conference (AAFC). Speedie secured a spot on the team and quickly became one of the top wide receivers of his time, teaming up with Dante Lavelli to form one of the most formidable receiving duos in professional football history.

Speedie showcased a graceful stride, perfect timing, and impressive control along the sideline. As Paul Brown’s main split-end threat, he skillfully ran sharp curl and post routes that caught defenses off guard, especially when they laid extra focus on Cleveland's strong ground game. His big hands and sharp tracking skills enabled him to catch passes while moving at full speed, transforming short throws into exciting long-distance touchdowns.

Speedie quickly made a big impact in the AAFC, playing a key role in helping the Browns secure all four AAFC Championships from 1946 to 1949. He was a standout receiver, leading the league in receiving yards twice—amassing 1,146 yards in 1947 and 1,028 yards in 1949—and topping the receptions chart for three straight seasons from 1947 to 1949. During the 1947 season, he even set a professional football record with an impressive average of 81.9 receiving yards per game.

When Cleveland joined the NFL in 1950, Speedie was right there with them. He caught 42 passes for 548 yards during the regular season and played a key role in helping Cleveland win the 1950 NFL Championship in their first year. He also earned Pro Bowl honors in 1950 and 1952, and in 1952, he led the entire NFL with 62 receptions for 911 yards and five touchdowns. Over his seven seasons in Cleveland, he was recognized twice as a First-Team All-Pro (1950, 1952) and also received three First-Team All-AAFC selections.

Following the 1952 season, a contract dispute with head coach Paul Brown prompted Speedie to leave the NFL for the Canadian Football League. He played three seasons in Canada with the Saskatchewan Roughriders and BC Lions before retiring from active play.

Speedie left Cleveland with 349 receptions for 5,602 yards and 33 touchdowns across 86 games. In 2020, he gained national recognition by joining the Pro Football Hall of Fame as part of the NFL's Centennial Class. That year, the franchise also honored him by adding him to the Cleveland Browns Ring of Honor.