Originally taken in the 2002 NHL Entry Draft by the New York Rangers, Nate Guenin would become a free agent following completing four years at Ohio State University. He would choose to sign with the Philadelphia Flyers in the summer of 2006.
Nate made his professional debut in the 2006-07 season with the Phantoms of the AHL. Later that season Guenin would make his NHL debut with the Flyers.
In the summer of 2009, Guenin signed as a free agent with the Pittsburgh Penguins.
On February 11, 2010, Guenin was dealt to the St. Louis Blues in exchange for defenceman Steve Wagner.
On July 2, 2010 he signed as a free agent by Columbus,though his time with the Blue Jackets would be short-lived. He was traded to the Anaheim Ducks on January 4, 2011, in exchange for Trevor Smith.
At the conclusion of the 2012-13 season, Guenin signed a one year contract with the Colorado Avalanche on July 5, 2013.