On March 30, 2010, the NHL's New York Rangers signed Talbot as a free agent. He was promoted to the Rangers on February 28, 2011, after playing the majority of the 2010–11 season with the Connecticut Whale of the American Hockey League (AHL) (he also played two ECHL games with the Greenville Road Warriors) and was returned to the Whale on March 3, 2011.
Talbot played the 2011–12 season with Connecticut, but after Connecticut was eliminated from the AHL playoffs, Talbot was added to the Rangers' Stanley Cup playoff roster. After the 2012–13 Whale season, he was again added to the Rangers' playoff roster.Talbot was again called up to the Rangers on October 15, 2013, after Martin Biron was demoted to the AHL, finding himself a place in the NHL for the first time as the backup to starter Henrik Lundqvist. Talbot made his on-ice NHL debut on October 24 in a 2–1 loss to the Philadelphia Flyers. His first NHL win came in his next game, against the Detroit Red Wings, on October 26, 2013, and he earned his first NHL shutout against the Montreal Canadiens on November 16, 2013. In the 2014 playoffs, Talbot twice entered to relieve Lundqvist en route to the Rangers' Eastern Conference title before ultimately falling to the Los Angeles Kings in the Finals.
For the 2014–15 season, Talbot began the year as the Rangers' backup goaltender, and in his first eight games played, he recorded three shutouts, matching his total from the entire previous season.
On February 3, 2015, Talbot became New York's temporary starting goaltender after Henrik Lundqvist suffered a ruptured blood vessel in his neck. Talbot started the Rangers' next 24 games until March 27, when Lundqvist returned to the line-up. During Lundqvist's absence, Talbot performed superiorly in net and went 17–4–3. In fact, Talbot ended the season with a lower GAA (2.21), and a higher save percentage (.926) than Lundqvist (2.25 GAA, .922 save percentage). For his remarkable efforts towards New York's Presidents' Trophy-winning season, he received the Steve McDonald Extra Effort Award on April 6.
Talbot was original expected to complete for the starting goaltender position with Anders Nilsson, but a poor start to the season resulted in Talbot being relegated to backup. By December, however, Talbot was performing much better and outplaying Nilsson.
On January 17, 2016, the Oilers signed Talbot to a three-year, $12 million contract extension. Nilsson was eventually traded to the St. Louis Blues, leaving Cam Talbot as Edmonton's #1 goalie.