He began his professional career at the local Swiss club FC Basel, playing four seasons in the first team before moving to Borussia Dortmund.

Degen played his youth football, together with his twin brother David, with local amateur club FC Oberdorf.

[8] Degen played his domestic league debut with the team in the home game in the St. Jakob-Park on 2 December as Basel were defeated 4–5 by Grasshopper Club.

[9] Basel started well into the second part of the season and during this period FCB played their best football, pulling away at the top of the table and subsequently achieved the championship title prematurely.

Just four days later they played in the cup final against Grasshopper Club winning 2–1 in extra time and they won the double.

[10] In his second season with the team Degen came to more playing practice, because right back Massimo Ceccaroni had retired from active football.

[12] In their 2003–04 season Degen became regular starter and scored his first goal for the team in the home game in the St. Jakob-Park on 26 July 2003.

But with two victories, 2–1 away against Ferencvárosi TC and 1–0 at home against Feyenoord, saw Basel rise to third place in the group table and advance to the knock-out stage.

In the round of 32 in the 2004–05 UEFA Cup, a home game in the St. Jakob-Park on 17 February 2005, Basel played a goalless draw against Lille OSC, but the return leg was defeated 2–0 and were eliminated.

[15] Basel completed all the 2004–05 Super League season's seventeen home games undefeated, winning thirteen and drawing four.

[16] In the first four seasons of his senior career Degen made 82 first team appearances in the Swiss Football League scoring four goals.

[17] Degen was then signed by Borussia Dortmund of the German Bundesliga and in three seasons at the club he made 68 first team appearances, scoring one goal.

[22] Degen made his competitive Liverpool debut in the third round of the Football League Cup in the 2–1 home win against Crewe Alexandra, during which he broke two of his ribs and punctured his lung in a collision with teammate Sami Hyypiä and was out for two months.

[23] On 12 November 2008, he made his first-team comeback in the 4–2 League Cup defeat at Spurs, only to suffer a broken metatarsal.

After 14 months into his Anfield career, Degen made his league debut in the 4–0 win over Burnley on 12 September 2009, coming on as a substitute for Glen Johnson at the hour mark.

On 22 September 2009, Degen started in Liverpool's 1–0 League Cup win against Leeds United at Elland Road.

[25] Degen got his first Premier League start in an away match against Fulham on 31 October 2009, in place of the injured Glen Johnson.

On 19 April 2010, Degen played the last 13 minutes of the home 3–0 win versus West Ham United at Anfield.

[30] Just a short time later, he made the request to the then Basel manager Thorsten Fink if he could keep fit with his home club's first team.

[32] At the end of the 2011–12 season, Degen won the Double, the League Championship title[33] and the Swiss Cup[34] with Basel.

Basel entered the Champions League in the group stage and reached the knockout phase as on 9 December 2014 they managed a 1–1 draw at Anfield against Liverpool.

[5] He has not been called up to the team since Ottmar Hitzfeld took over as the new manager due to his preference to play younger players like Stephan Lichtsteiner and Valon Behrami.