Meyers joined the SNL cast in 2001. In 2005, he was promoted to writing supervisor and in January 2006 he became co-head writer, sharing the role with Tina Fey and Andrew Steele. In 2004, he auditioned to co-anchor "Weekend Update" with Fey, but lost out to Amy Poehler. With Fey's departure, Meyers became head writer for the 2006–2007 season and also took on the role of Weekend Update co-anchor with Amy Poehler. Since Poehler left the show during the 2008–2009 season, Meyers has anchored solo. Meyers is currently the longest tenured Saturday Night Live cast member, having been a member since Season 27.
Outside of SNL Meyers has appeared with Brendan Fraser in the 2008 3D film Journey to the Center of the Earth. Meyers is currently writing and will star in a movie called Key Party. He also starred in the 2004 comedy See This Movie with John Cho. Meyers has hosted the Webby Awards twice, in 2008 and 2009. Meyers also hosted the 2010 and 2011 ESPY Awards on ESPN. In 2011, Seth Meyers was the keynote speaker at the White House Correspondents Association Dinner on April 30.