Pennington graduated from the Webb School of Knoxville where he excelled in football and basketball. He went on to play in college for Marshall University, where he set school records in several passing categories and led the school to three Mid-American Conference titles. He finished 5th in Heisman voting during his senior year at Marshall. He was selected by the Jets in the first round and eighteenth overall pick of the 2000 NFL draft.

In a 2003 preseason game against the New York Giants, Pennington injured his non-throwing hand, which forced him to sit out the first six games of the 2003 NFL season. The Jets lost their first four games that season and would end up with a 6-10 record. The Jets and Pennington rebounded in 2004, starting the season 5-0 before finishing at a 10-6 mark. Pennington injured his rotator cuff during a Week 9 game against the Buffalo Bills and was forced to miss three games. Second string QB Quincy Carter was 2-1 in Pennington's absence. After returning to action with a rout of the Houston Texans, Pennington struggled the rest of the season and there was speculation that Pennington's shoulder was not fully healed. After a scuffle with the New York media and losses to the New England Patriots and St. Louis Rams, the Jets still managed to earn a Wild Card berth. Pennington answered speculation that his shoulder was ailing with a sterling 20-17 overtime win against the AFC West Champion San Diego Chargers. This win came in the first round of the playoffs and Pennington's numbers were impressive: 23-33 for 279 yards and two touchdowns. Pennington then faced the 15-1 Steelers at Pittsburgh. Despite the Jets offensive struggles and being in a 10-0 hole, the Jets rallied to score 17 unanswered points. However, Pennington would see his season end with his kicker Doug Brien missing two crucial game winning field goals. The Steelers would go on to win in overtime, the third overtime in a row for Pennington and the Jets.

Pennington underwent surgery on his right shoulder in Birmingham, Alabama on February 4, 2005. It was later revealed that he had suffered a substantial tear in the right rotator cuff, as well as a large bone spur on that shoulder. A dismal performance against the Kansas City Chiefs on September 11 and a lackluster one against the Miami Dolphins the following week have led to speculation that the shoulder has yet to fully heal, but both Pennington and Jets coach Herman Edwards deny this, citing rather a lack of preseason practice and Pennington's less-than-full grasp of new offensive coordinator Mike Heimerdinger's plays. On September 25, 2005 against the Jacksonville Jaguars, Pennington once again suffered injury, although he re-entered the game later and almost led the Jets to victory despite not throwing well. However tests later showed another tear in his rotator cuff.

On October 6, 2005, Pennington once again underwent surgery to repair his right shoulder. The team remains optimistic that with proper rehibilitation, he will return for the 2006 season.

In the midst of the eventually-resolved labor talks of February-March 2006, Pennington restructured his contract with the New York Jets, ensuring that he remains with the team for at least the upcoming 2006 season. Pennington is reported to have taken a significant cut in pay, with the amounts lost regainable by way of achievable incentives, however the New York Jets organisation do not comment on contractual issues.