In 1998, Seo was signed as a free agent by the New York Mets. After an excellent first year of professional play, Seo underwent reconstructive surgery on his elbow in 1999. He did not pitch again until 2001. On July 21, 2002, Seo made his major league debut with a scoreless inning of relief against the Cincinnati Reds. In 2003, Seo spent the entire season with the Mets as a starting pitcher. He logged 188 innings pitched and 31 games started, both tops among rookie pitchers in the National League that year. In 2004, Seo struggled, splitting his time between the Mets and the AAA Norfolk Tides.

When he first pitched in the major leagues, he had two pitches - a fastball which tops out at 91-92 miles per hour (he threw in the mid-90s before Tommy John surgery), and a deceptive changeup in the mid 80s. Not being able to throw as hard as earlier in his career meant it was important for Seo to maintain a high degree of control over his pitches which, on occasion he was unable to do. This, along with Seo's reluctance to change his pitching mechanics, led to confrontations with Mets' pitching coach Rick Peterson.

However, in 2005, Seo finally seemed to have taken heed of this advice, developing a slider, splitter and curveball. The Mets' surplus of pitchers resulted in his spending much of the year at Norfolk. However, he was called up to the majors in early August 2005, and pitched extremely well.

On January 4, 2006, Seo was dealt to the Los Angeles Dodgers along with Tim Hamulack in exchange for relievers Duaner Sanchez and Steve Schmoll. On June 26, he was traded by the Dodgers, along with catcher Dioner Navarro and outfielder Justin Ruggiano to the Devil Rays in exchange for pitcher Mark Hendrickson and catcher Toby Hall. Seo made his debut with the Rays on June 28, 2006 against the Florida Marlins, pitching two scoreless innings.