Born in Houston, Texas, Isbell was the second son of Adger and Sarah Isbell. His older brother Cody was also a football player for Purdue and his two younger brothers also played college football: William Adger "Dub" Isbell Jr. at Rice Institute and Larry Isbell at Baylor University.
Isbell was selected in the first round of the 1938 NFL draft by the Green Bay Packers, the seventh overall pick. When he arrived in Green Bay, the Packers already had an All-Pro tailback, Arnie Herber. who had led the Packers to the NFL championship in 1936. Coach Curly Lambeau alternated Isbell and Herber and occasionally used them in the same backfield, with Isbell at halfback. This "platooning" allowed Isbell to learn Lambeau's offense, the Notre Dame Box. Isbell was a very accurate passer and a good runner and he led the Packers in rushing and passing in his rookie year. The Packers came in first in the West and faced the New York Giants in the championship game at the Polo Grounds. Isbell rushed 11 times for 20 yards and was 3 of 5 passing for 91 yards, but the Giants prevailed, 23–17. In 1939, the Packers used the same attack and again Isbell led the team in rushing while catching 9 passes as well. The Packers again won the Western division and faced New York in a rematch from the year before. This time the game was played in Milwaukee and Green Bay crushed the Giants, 27–0, with Isbell throwing a 27-yard touchdown pass.
From 1940 to 1942, the Packers finished second in the West to the Chicago Bears each year. Isbell became a more accomplished passer during this time, connecting regularly with Don Hutson in record-setting frequency. In 1941, Isbell set an NFL record for yards passing with 1,479 and led the league in completion percentage (56.8%) and touchdown passes with 15 (10 to Hutson). The Packers finished the season tied with Chicago, but lost to the Bears in a divisional tiebreaker playoff, 33–14. In 1942, Isbell surpassed his own record with 2021 yards passing and set a new record with 24 touchdown passes. Hutson also set NFL records with 74 receptions, 1,211 yards receiving and 17 touchdowns (Hutson's touchdown mark was matched by Elroy Hirsch in 1951 and stood until 1984). Still, the Packers finished second to Chicago, who were 11–0 in the regular season.
After the 1942 season, Isbell quit the NFL after just 5 years, He finished with 5,945 yards passing, 61 touchdowns, and 52 interceptions.
Isbell started out at Purdue as an assistant coach in 1943 and took over as head coach in 1944. He coached there for three years with a 14–14–1 record. In 1947, he became a pro coach for the Baltimore Colts in the All-America Football Conference. He lasted for 2⅔ seasons, resigning prior to the fifth game in 1949. His one claim to fame from those years in the AAFC was he was the first coach of Y. A. Tittle, who went on to great success in the NFL. After a few more years as an assistant coach in the NFL coaching the Chicago Cardinals under head coach Curly Lambeau, and later the Dallas Texans, Isbell quit football for business in the mid 1950s.