During the second game of the 2006-07 Guinness Premiership season against Worcester Warriors on Friday, 8 September, Wilkinson was helped from the pitch after 47 minutes with a knee injury incurred when one of his team members fell on him after he was tackled. A scan confirmed that he had torn the medial ligament of his right knee. He returned to play a full 80 minutes in the 26–21 win against leaders Bristol on Friday, 3 November, kicking a conversion, a drop-goal and two penalties. It was reported on 9 November that Wilkinson suffered a lacerated kidney during the match. He returned from this injury in the Premiership game against Leicester Tigers on 27 January 2007, coming off the bench after 37 minutes. On 29 January 2007, Wilkinson was selected at fly-half in the starting line up for England in their 2007 Six Nations Championship opener against Scotland. England comprehensively beat Scotland 42–20 to regain the Calcutta Cup, Wilkinson making an impressive return, scoring 27 points with five penalties, two conversions, a drop goal, and a try. This broke the previous Calcutta Cup individual record of 24, set by Rob Andrew. Wilkinson was awarded the RBS Man of the Match as adjudicated by BBC commentator, Brian Moore. In the following match against Italy at Twickenham, Wilkinson scored 15 points to become the highest individual point scorer in the history of the Five/Six Nations with 421 points.
In the 2007 Rugby World Cup Final, on 20 October at the Stade de France, South Africa won the Webb Ellis Cup in a game where Wilkinson slotted home 2 penalties, but missed 2 drop kick attempts. He was one of only four players to have started both the 2003 and 2007 Rugby World Cup Finals, the other three being Phil Vickery, Jason Robinson and Ben Kay.
Because of a succession of injuries – affecting his knee ligaments, arm, shoulder and kidney – Wilkinson's international career was severely disrupted. He did not appear again for England until 1,169 days after the 2003 Rugby World Cup triumph, for the opening game of the 2007 Six Nations Championship against Scotland on 3 February 2007. In his comeback international match, Wilkinson scored 27 points (a record in the Calcutta Cup) in a full house (scoring points by all four possible methods), and was proclaimed Man of the Match.
The following week against Italy, he became the highest point-scorer in the history of the Five/Six Nations Championship (he has since been overtaken by Ronan O'Gara of Ireland). On 6 October 2007, he also became the highest point-scorer in the history of the Rugby World Cup, kicking four penalties to overtake Scotland's Gavin Hastings in a quarter-final against Australia.
Wilkinson is widely known as a teetotaler, but broke that habit after England lost to South Africa in the 2007 Rugby World Cup Final. Wilkinson seeks to eat natural foods, avoiding toxins.