Cissé began his career with Génération Foot and Douanes Dakar before transferring to the French side Metz in summer 2005. After only one month during the 2005–06 season, he left Metz and was loaned to French side Cherbourg. During the season, Cissé played 26 matches and scored 11 goals for the Normandy club. After the season, Cissé returned to Metz for a further two years before being loaned again to Châteauroux in January 2008 and before returning to Metz in July 2008 for a third stint.

Cissé signed for German Bundesliga side Freiburg on 28 December 2009 for a fee of €1.62 million. He initially became a transfer target for Freiburg in the summer of 2009 after he scored a goal and assisted on another in a 2–1 friendly win for Metz over the club. However, a transfer fee could not be agreed upon at the time. Hannover 96 also expressed interest in the player. In his first partial season at Freiburg, Cissé appeared in 16 matches, scoring six goals.

Cissé made his international debut for Senegal on 12 August 2009, in a friendly away to Congo DR, scoring two goals as Senegal emerged victorious 2–1. Cissé scored a hat-trick in his fourth appearance for the national side, as Senegal ran away to a 7–0 victory over Mauritius on 9 October 2010 in a qualifying match for the 2012 Africa Cup of Nations. Cissé also captained the Senegal team from 2012 to 2013. Cissé’s most recent Senegalese goal was against Botswana in November 2014, his 16th international goal.

On 21 January 2012, Cissé signed for Newcastle United on a five-and-a-half-year deal for an estimated fee in the region of £9.3 million, linking up with fellow Senegal striker Demba Ba in the process. He was subsequently handed the number 9 shirt, formerly worn by Newcastle legend Alan Shearer. On 5 February, Cissé made his debut for Newcastle in the 2–1 league win against Aston Villa at St James’ Park. He replaced the injured Leon Best in the 14th minute before scoring the winning goal in the 71st minute with a breath-taking volley, chesting it before volleying with his left into the top left corner of the net. On 11 February, he made his first start for the club in the 5–0 away league defeat against Tottenham Hotspur at White Hart Lane. On 25 February, he scored in the sixth minute in a 2–2 home draw against Wolverhampton Wanderers. On 25 March, he scored two first-half goals in Newcastle’s 1–3 league victory against West Bromwich Albion at The Hawthorns, but he was denied a hat-trick early in the second half by a save by West Brom goalkeeper Ben Foster. Cissé’s brace against West Brom made him the quickest player since Les Ferdinand to hit the five-goal mark for Newcastle.

Cissé scored his sixth and seventh goals, against Liverpool, in a 2–0 home win. He scored a third consecutive brace at Liberty Stadium in a 0–2 away win against Swansea City on 6 April, bringing his tally to nine goals in eight matches. This made him Newcastle’s most prolific goals per-game goalscorer of all-time, ahead of Hughie Gallacher. On 9 April, he scored his tenth goal in nine matches for Newcastle against Bolton Wanderers in a 2–0 home win. On 21 April, Cissé scored his 11th goal in ten matches during a 3–0 win against Stoke City. He then managed to score his 12th and 13th Premier League goals in a 0–2 win against Chelsea at Stamford Bridge on 2 May 2012, the second of which he curled the ball with the outside his foot from 37 yards out. Cissé described the goal as the best of his career, and was subsequently chosen as the BBC’s Goal of the Season. At the end of his first half season with Newcastle, he was known for his consistent goalscoring, with astonishing goals firing the North East club into a fifth place spot in the table.

On 4 July 2012, it was reported that Newcastle had blocked an offer from the Senegalese Football Federation for Cissé to play for Senegal at 2012 Summer Olympics in London. The reason behind the decision was that Newcastle wanted their key striker fit for a tough season ahead, playing European football. Cissé scored his first goal in the 2012–13 season with a header in the League Cup against Manchester United. He scored Newcastle’s third goal in their Europa League defeat of Bordeaux on 4 October 2012, Newcastle’s 100th match in European competition. He scored his first Premier League goal of the season in a 2–1 win over West Bromwich Albion on 28 October 2012, as a shot taken by Sammy Ameobi deflected off Cissé and into the net. The striker’s scoring was scarce throughout the opening four months of the season, only scoring his second league goal of the season on 28 November, a 2–1 away defeat to Stoke City.

Cissé started against Everton alongside Shola Ameobi and scored a header in the second minute in a 2–1 defeat on 2 January 2013. Cissé scored a spectacular 25-yard volley in Newcastle’s 4–2 win over Southampton on 24 February, helping the club come from behind to secure a crucial victory over fellow relegation strugglers. Cissé scored an injury time winner at home to Stoke City on 10 March, sending Newcastle into 13th place. On 14 March, in the second leg Europa League Round of 16 tie at home to Anzhi Makhachkala, Cissé headed in a 94th-minute winner as Newcastle progressed to the quarter-finals with a 1–0 aggregate victory.

On 25 September 2013, Cissé opened his account for the 2013–14 season in a 2–0 win for Newcastle against Leeds United in the third round of the Football League Cup. Cissé scored his first Premier League goal of the season in a 5–1 home rout of Stoke City on Boxing Day, converting a late penalty.

On 22 March 2014, he scored a last-minute winner to claim all three points for Newcastle in a 1–0 victory at home to Crystal Palace, only his second league goal of the season. Cissé’s season finished on 19 April against Swansea City as he limped off in the 21st minute. It was revealed by Newcastle that Cissé had broken his kneecap and that he had undergone surgery on the injury.

After breaking his knee cap against Swansea in April 2014, Cissé returned to France to recover from his injury. In June, it was revealed that Cissé would return from his injury earlier than expected and would return to Newcastle for pre-season training along with the rest of the first-team squad. On 10 September 2014, Newcastle manager Alan Pardew confirmed that Cissé would return to the Newcastle squad for their home match against Hull City on 20 September.

On 7 March 2015, Cissé was handed a six-match ban by the FA after a spitting incident with Manchester United defender Jonny Evans, and one more for elbowing Everton’s Séamus Coleman. All together, it was a seven-match ban. Cissé returned to the team as a second-half substitute in Newcastle’s 1–1 draw with West Brom on 9 May.

Cissé started the first match of the season at home against Southampton, scoring after chesting the ball in from close range to make the score 1–1. Despite scoring, however, he was substituted for new signing Aleksandar Mitrović, who had recently joined from Anderlecht. The match finished in a 2–2 draw. On 28 November 2015, he opened the scoring in an eventual 5–1 loss to Crystal Palace. Cissé’s final goal for the club came in a 2–2 draw against Liverpool, on 23 April 2016.

On 9 July 2016, it was announced that Cissé had joined Chinese Super League club Shandong Luneng for an undisclosed fee. He scored on his second appearance for the club, in an eventual 4–1 win over Hangzhou Greentown.

On 31 August 2018, he has signed with Alanyaspor of the Turkish Süper Lig. He made his debut against Göztepe on 1 September 2018 and he scored his first goal against Kasımpaşa on 23 September 2018 and in the same game he scored one more goal and Alanyaspor won the game 2–1.

On 28 April 2019, Cissé was involved in a coach crash which killed Alanyaspor team mate Josef Šural. Cissé escaped with minor injuries.

On 1 October 2020, Fenerbahçe announced the signing of Cissé.