After acquiring a 3–0 record in smaller shows, Cantwell made his WEC debut at in 2007 against Brian Stann, where he suffered a quick TKO loss. After two subsequent victories, Cantwell again faced Stann, WEC Light Heavyweight Champion at WEC 35 and won by TKO in the second round. Shortly after Cantwell took the title, the WEC dropped both its Light Heavyweight and Middleweight divisions, making Cantwell the final WEC Light Heavyweight Champion.
Later that year, Cantwell signed with the UFC, which is owned by the WEC's parent companyZuffa. Cantwell faced fellow UFC newcomer Razak Al-Hassan at an earned a technical submission victory by dislocating Al-Hassan's elbow in an armbar, causing referee Mario Yamasaki to stop the fight. Cantwell's celebration of the victory and post-fight comments sparked some criticism when he said, "I've been waiting so long to do that, you have no idea". He later apologized for his behavior. He fought Luiz Cané at UFC 97, but lost the fight via unanimous decision. Cantwell would next face Brian Stann at UFC Fight Night 13 in what would be their third fight. In their previous fight Cantwell had defeated Stann to become the last reigning WEC Light Heavyweight Champion. Cantwell lost the rubber match via unanimous decision. Cantwell was expected to face Vladimir Matyushenko on January 2, 2010 at UFC 108, but pulled out of the bout for undisclosed reasons. Since there was no time to find a suitable replacement to face Matyushenko, the bout was called off. UFC President Dana White mentioned at the UFC 108 Pre-Fight Press Conference that Cantwell may never fight again, but refused to disclose what Cantwell's medical issues were. With the questions surrounding his medical condition apparently cleared, Cantwell was expected to face UFC newcomer Ricardo Romero on July 3, 2010 at UFC 116. However, for unknown reasons, Cantwell was replaced by Seth Petruzelli. Cantwell was expected to face Stanislav Nedkov on October 16, 2010 at UFC 120. However less than 48 hours before the event, Cantwell was forced off the card after suffering a knee injury during a pre-fight workout. With no time to find a suitable opponent for Nedkov, the bout was cancelled. Cantwell faced Cyrille Diabaté on March 3, 2011 at and lost the fight via unanimous decision. Cantwell dropped to Middleweight for his next fight and faced Mike Massenzio on October 8, 2011 at UFC 136. He lost the fight via unanimous decision. Cantwell faced Riki Fukuda on February 26, 2012 at UFC 144. He lost the fight via unanimous decision and was subsequently released from the promotion.
