After leaving Oregon State University, Lowe played for the San Francisco 49ers during the 1959 pre-season. However, Lowe was unable to make the team and was released before the regular season began. He returned to Los Angeles, California to get a job to support his wife, Sophia Lowe. He took a job in the mailroom for the Carte Blanche Credit Card Corporation, owned by the Hilton family.
In 1960, Barron Hilton, son of famed hotel magnate Conrad Hilton, was the original owner of the Los Angeles Chargers, a start-up team in the newly formed American Football League. The Chargers General Manager, Frank Leahy, asked Lowe to come out to the Chargers training camp on the basis of his talents at Oregon State a few years back. Lowe joined the Chargers as a free agent. He returned his first touch of the football in the AFL for a 105-yard touchdown in the Chargers' first-ever exhibition game and led the team in rushing with 855 yards on 136 carries (6.3 yard average) and also had 23 receptions for 377 yards. In 1961, with the team now based in San Diego, Lowe had the Chargers' longest run from scrimmage with an 87-yard run, a record that still stands today.
Lowe was the UPI and Sporting NewsAmerican Football League MVP in 1965 with 1,121 yards rushing (14-game schedule). He was also a three-time all-American Football League selection. Lowe set a pro football record with six games in which he gained 100 or more yards on 14 or fewer carries. He has the AFL's all-time highest rushing average, at 4.89 yd/carry, and his career rushing total of 4,995 yards is second best all-time in the AFL. He is also one of only twenty players who were in the AFL for its entire ten-year existence.