Henchoz earned 72 caps for Switzerland from his debut in 1993. He played for the country at Euro 96 and Euro 2004. He was expected to play in the 2006 FIFA World Cup, but due to health problems he retired from international football on 31 March 2006.

In June 1997, he turned down an opportunity to join Manchester United, instead signing for Blackburn Rovers for a fee of £3 million. Henchoz enjoyed a very successful debut Premiership season as Rovers finished sixth in 1997–98, although they were then relegated at the end of the 1998–99 season. Henchoz remained a Premiership player after being purchased for £3.5 million by Liverpool.

At Liverpool, Henchoz became a regular member of the first team during his five-and-a-half year stay at Anfield. Henchoz proved to be an inspirational signing and was popular with the Liverpool fans. He formed an effective central defensive partnership with Sami Hyypiä. This partnership played an important part in Liverpool’s historic cup treble in 2001, although it was Henchoz’s clumsy challenge on Martin O’Connor in the 90th minute of the League Cup final against Birmingham City that led to extra time (the match itself was only settled on penalties). Henchoz is also remembered for inadvertently blocking a goalbound Thierry Henry shot with his arm in the 17th minute of that year’s FA Cup final, Liverpool then went on to win the match with two Michael Owen finishes.

When Rafael Benítez replaced Gérard Houllier as manager, his decision to try versatile English defender Jamie Carragher in partnership with Hyypiä spelled an end to Henchoz’s Anfield career. Carragher, previously employed as a full-back, was a revelation at centre back and Henchoz consequently joined Celtic on a six-month contract in January 2005.

Upon the expiration of his Celtic contract, Henchoz opted to move back to the Premier League, signing a one-year contract with newly promoted Wigan Athletic. He made 26 league appearances during the 2005–06 season as the club exceeded expectations with a top half finish. Henchoz also started for Wigan in the 2006 Football League Cup Final.

In December 2015, he was appointed assistant manager of Neuchâtel Xamax FCS. On 6 February 2019 the club announced, that they had sacked Michel Decastel and Henchoz would take charge of the club for the rest of the season. At the end of March 2019 the club confirmed, that Henchoz would leave his position at the end of the season.

On 27 May 2019, Henchoz was appointed manager of FC Sion for the upcoming 2019–20 season. He resigned on 4 November 2019 following a 0–3 loss to FC St. Gallen, which was the 5th loss in 6 league games.