Behrami started out playing football with Swiss club sides FC Stabio, FC Chiasso and FC Lugano. After a number of impressive appearances with Lugano, he was signed by Italian team Genoa in the 2003–04 season, and played for them in the Serie B championship. In January 2004 he joined Udinese along with Rodrigue Boisfer in exchange for Mohammed Gargo and Vittorio Micolucci, in flopped transfer price in co-ownership deal to create “paper” profit.

After an impressive season with Verona, Lazio signed him on 25 July 2005, as first a co-ownership deal for €2.7 million. and Lazio bought him outright in January 2006, for the same price.

Despite his clearance hitting Rodrigo Taddei’s head and ricocheting into Lazio’s goal to concede their first goal of the match, his 92nd minute winning goal etched Behrami’s name into Lazio’s history books as they won the Derby della Capitale on 19 March 2008 and virtually finished the Scudetto hopes for rivals Roma.

On 23 July 2008, West Ham United signed Behrami from Lazio, with the player signing a five-year contract for a fee of £5 million. Behrami made his debut for West Ham in the 2–1 home win over Wigan Athletic on 16 August 2008. His versatility would see him become a vital part of West Ham’s midfield, having begun the season as a stand in for captain Lucas Neill at right back. He scored his first goal for West Ham in the 1–0 away win against Sunderland on 23 November 2008. During the home win over Manchester City on 1 March 2009, he suffered an anterior cruciate ligament injury in his left knee that required oxygen to be administered on the field during a six-minute break in play. His knee and ankle twisted badly when his studs caught in the turf resulting in a premature end to his 2008–09 season.

Behrami made his comeback as a substitute on 12 September 2009 against Wigan Athletic. His return was interrupted by injury again for a month from November. He scored his first and only goal of the 2009–10 league campaign with the opener in a 3–0 home win over relegation rivals Hull City on 20 February 2010.

On 21 June, in the 2010 World Cup, after appearing to elbow Chilean player Arturo Vidal, Behrami was sent off with a red card in the second Group H match against Chile and became the first Swiss player to be sent off in a World Cup match.

On 26 January 2011, Behrami moved to Fiorentina for an undisclosed fee, signing a three-and-a-half-year contract. He made his debut with Fiorentina on 29 January 2011, in a Serie A fixture against his former team Lazio.

On 17 July 2012, Behrami and his Fiorentina teammate Alessandro Gamberini were signed by Napoli for undisclosed fees.

On 31 July 2014, Behrami flew into Germany to complete a medical ahead of his €4.5 million move to Hamburg. The subsequent bonuses could raise the fee to €6.5 million based on 20 appearances in his first season. He committed to a three-year contract with an option for a fourth.

On 11 July 2015, Behrami watched on as his teammates drew 2–2 with AFC Wimbledon, later that afternoon the club confirmed Behrami signed a three-year contract with Watford.

On 16 August 2017, Behrami signed a two-year deal with Italian club Udinese, who are owned by the Pozzo family just as his previous club Watford.

In July 2018 it became known that Behrami married his girlfriend, Swiss alpine ski racer Lara Gut, after only having been dating for a few months.

In July 2019, he joined Swiss club Sion. On 3 October 2019, his contract with Sion was terminated by mutual consent.

On 2 January 2020, Behrami joined Genoa for the second time. On 5 January, he came on in his debut as a substitute in a 2–1 home win against Sassuolo in the 72nd minute.

In September 2020 he was one of the 10 Genoa players who tested positive for COVID-19.