The National Football League's Washington Redskins picked Isbell in the first round of the 1952 NFL draft (He had the same draft position, #7, as his brother Cecil, making them perhaps the only pair of brothers to be drafted at the exact position), but he opted to sign with Major League Baseball's Boston Red Sox. The club sent him straight to AAA and he hit .266/.360/.337 for the Louisville Colonels in 1952, very similar numbers to the other Louisville catcher, former Major Leaguer Al Evans. Back with the Colonels in 1953, Isbell was even better at .317/.386/.397 in 47 games while fielding .995; he outhit Pete Daley, the starter at catcher. In fact, he had the best average of any Louisville batter with 25 or more games player, ahead of Charlie Maxwell, Harry Agganis, and Ken Aspromonte, among others. He also played three games for the Fort Worth Panthers, hitting .200.
In 1977, Baylor began handing out the Larry Isbell MVP to its top baseball player. Isbell is a member of both the Baylor Hall of Fame and Texas Sports Hall of Fame. Isbell was living in Waco, Texas and working as a car salesman in Clifton, Texas when he died of a heart attack in 1978. In 2006, Baylor University hung banners around Floyd Casey Stadium honoring their best football players, including Larry Isbell.