Tewksbury was drafted by the New York Yankees in the 19th round of the 1981 draft. He played for the Yankees for two years, before being sent to the Chicago Cubs. As a free agent in 1988, he signed with the St. Louis Cardinals, where he would stay until 1994. Again a free agent, he went to the Texas Rangers for a year. In 1996, he signed with the San Diego Padres for one more year. He then played for two years with the Minnesota Twins, but the shoulder problems effectively ended his baseball career after that.

Due to the shoulder and arm problems he would face over the course of his playing career, Tewksbury became known as an excellent control pitcher. His best year was 1992, in which he went 16-5 on the season and had a 2.16 ERA in 233 innings pitched. He also started the All-Star Game for the National League and was third in the Cy Young Award voting that year. His injury problems would continue to mar his success from that point forward, with his best post-Cardinals year being in San Diego, where he would help the Padres capture the NL West division title.

In 1997, the ever-crafty Tewksbury threw an Eephus pitch, joining an elite few who have thrown the "junkiest pitch in baseball." He threw it to power-hitter Mark McGwire, no less. (McGwire grounded out on the pitch - twice.)

In 2004, his first year of eligibility, Tewksbury received less than 5f the vote (he received no votes; the threshold was 25) from the Baseball Writers Association of America (BBWAA) for induction into the Baseball Hall of Fame, thus becoming ineligible to appear on future BBWAA ballots. However, he may eventually be considered for induction into the Hall by the Veterans Committee once 20 years have passed from his date of retirement (therefore, in the year 2019), in accordance with current Hall of Fame rules (enacted in 2001).

During and after his baseball career, he became well-known for his philanthropy. He has done a lot of work for the Boys and Girls Club of America, as well as hospital visits for sick children. He was very popular among his fans and peers, his Texas manager saying "He’s a true professional on and off the field - and a pleasure to have in the clubhouse."

Tewksbury still lives in New Hampshire, continuing his charitable work, as well as appearing as a commentator for Boston Red Sox coverage on the New England Sports Network.

Tewksbury is now a sports psychologist for the Boston Red Sox.