On November 27, 2005, Fitzpatrick made his professional regular season debut after entering the game in the second quarter against the Houston Texans to replace injured veteran journeyman Jamie Martin. Fitzpatrick led the Rams from a 24–3 halftime deficit to a 33–27 overtime win, throwing for 310 yards and three touchdowns, completing 63. 3% of his passes and 117. 4 QB rating for the game. He earned NFC Offensive Player of the Week for his effort. This made Fitzpatrick one of only eight players who passed for more than 300 yards in their NFL debut. The win earned him the next three starts, making Fitzpatrick the first Harvard quarterback to start an NFL game. Fitzpatrick was unable to duplicate his debut performance in the games he started with the Rams coming two weeks later in a 27–13 loss to the Minnesota Vikings in which he threw for 235 yards, no touchdowns, and five interceptions for a QB rating of 32. 4 for the game. He was replaced by Martin after halftime the following week, after struggling in a home game against the Philadelphia Eagles in which he completed just 41. 7% of his passes for a total of 69 yards. He finished his rookie season with 76 pass completions of 135 pass attempts (56. 3%) for 777 passing yards with four touchdowns and eight interceptions in four games with three starts.