On January 20, 2009, Regin was called up and made his NHL debut in a 3-2 win against the Washington Capitals. He was sent back down to Binghamton the next day. On January 29, 2009, Regin played in his third NHL game and scored his first NHL goal, a game winner, against Chris Mason of the St. Louis Blues. On July 29, 2010, the Senators resigned Regin to a two-year, $2 million contract extension. On February 19, 2011, in a game against the Toronto Maple Leafs, Regin suffered a dislocated shoulder after being pushed into the boards by Toronto's Joey Crabb and needed season-ending surgery. On April 5, 2012, Regin was re-signed to a one-year, one-way contract by the Senators.