Clerc was left out of the French squad for the 2006 Autumn Internationals, but was called up as a replacement for Cédric Heymans for the match against Ireland during the 2007 Six Nations Championship. In a closely contested match at Croke Park, Clerc scored a last-gasp try to snatch a 20-17 victory for France.
He scored 5 tries during the first two games of the 2008 Six Nations Championship against Scotland and Ireland. In a post-match interview after the match against Ireland Clerc stated to the French TV channel France 2 that he "never would have been able to score a hat-trick if Shane Horgan had been playing." Horgan and Clerc have had a long rivalry and, unfortunately for Ireland, Horgan was unfit to play. In the 2007 RBS 6 Nations tournament Vincent scored a last gasp try against Ireland. In the last game of that series of games Vincent Clerc helped France to trounce Scotland to give them the title.
During the 2008 6 Nations, media attention focused on the final match of the tournament, where Clerc and Shane Williams would play as opposite numbers. Both had scored five tries so far in the tournament, but ultimately the match, dubbed as the "Big battle of the little people" was won by Wales, with Williams scoring one final try in the competition.
Clerc ruptured the ligaments in his left knee while playing for Stade Toulousain against ASM Clermont Auvergne in April 2008. He made his club comeback in December 2008, against Mont-de-Marsan, and was recalled to the national squad for the summer 2009 tests.
Clerc was selected in the squad for the 2011 Rugby World Cup in New Zealand, and was one of the stars of the tournament. He played every game for France and posed a constant threat on the right wing. He scored six tries for the tournament, three of them against Canada, to finish the tournament as joint top try-scorer with England's Chris Ashton.
On November 17, 2012, against Argentina in Lille, Clerc scored two tries to take his overall international tally to 34 tries, overtaking Philippe Saint-André to become France's second highest try scorer. France won 39-22.