Barry Wesson was drafted by the Houston Astros in the 14th round of the 1995 MLB Amateur Draft. Wesson signed on to play in the Astros organization. He spent 1995 mostly at the Rookie level. He then spent the following five years playing at the A level. It was not until 2001 that Wesson played most of the season in AA. On October 15, 2001, Wesson was granted free agency, only to be resigned by the Astros less than a month later. In 2002, Wesson hit .293 in AAA and was then called up to the majors. In 20 at bats for the Astros, Wesson hit .200. That year, Wesson was acquired off waivers by the Anaheim Angels. In 2003, Wesson was again called up, hitting .182 in 11 at bats. After the 2004 season, he was granted free agency and once again signed with the Astros. He spent the 2005 season in the minors. After the season, Wesson was granted free agency and decided to retire.
At the time of his retirement, Wesson had a career batting average of .194 with one home runs in 31 at bats. He had four runs batted in during this time. His lifetime fielding percentage is 1.000.