Greene was drafted by the Detroit Lions in the fifth round (35th overall pick) of the 1944 NFL Draft. As a rookie in 1944, Greene appeared in nine games, five of them as a starter. He was used principally as a blocking back. For the 1945 season, the Lions' head coach Gus Dorais moved Greene to the end position after being impressed with his speed. Greene started all 10 games for the Lions at the end position in 1945. He led the 1945 Lions in receiving with 26 receptions for 550 yards (21.2 yards per catch) and five receiving touchdowns. He also ranked fifth among all NFL players in receptions, receiving yards, and yards per catch during the 1945 season. Greene's production fell off during the 1946 season, as he appeared in all ten games, but only started two games. The highlight of Greene's 1946 season came in a 17-7 victory (the Lions' only victory in 1946) over the Pittsburgh Steelers on November 10, 1946. In that game, Greene caught a pass from Dave Ryan at midfield and ran the remaining 50 yards for a touchdown. The play, good for an 88-yard gain, was the longest pass play in the NFL during the 1946 season and the longest in Detroit Lions history up to that time. Even with the reduced playing time, Greene's 22 receptions in 1946 ranked eighth in the NFL. During the 1947 season, Greene was the Lions' leading receiver for the third straight year. He appeared in 12 games (six as a starter) and caught 38 passes for 621 yards (16.3 yards per catch). He ranked sixth in the NFL in both receptions and receiving yards. Greene's longest reception of the 1947 season was a 47-yard gain on a pass from Roy Zimmerman in a 35-7 victory over the New York Giants. Greene acquired the nickname "the Cinderella Kid" while playing for the Lions, a reference to "his rise to stardom after comparative obscurity while a lineman in college and early in his Lions' career." In 1948, Greene led the Lions in receiving yards for the fourth consecutive season. He appeared in 12 games (five as a starter) and caught 25 passes for 595 yards and five touchdowns. His average of 23.8 yards per reception was the best in the NFL. The 1948 Detroit Lions season was notable for the racial integration of the team. African-American halfback Mel Groomes joined the Lions in 1948, as did African-American end Bob Mann. Mann and Greene, both University of Michigan alumni, led the Lions' receiving corps.