Cissé began his career with AS 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 games 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 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.
During the 2010–11 Bundesliga season, his first full season with Freiburg, Cissé was second in the league in goals scored, only behind Mario Gómez of Bayern Munich, who scored 28. Cissé also set a club and league record; his 22 goals during the course of the season set the single-season goal record by a Freiburg player, as well as set the record for the most goals scored by an African in a single Bundesliga season. The record was previously held by Tony Yeboah, who scored 20 goals with Eintracht Frankfurt in 1992–93. That same season, Cissé won the EFFIFU award for being the most efficient striker in the league.
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 games. 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 games for Newcastle against Bolton Wanderers in a 2–0 home win. On 21 April, Cissé scored his 11th goal in ten games 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 FA 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 game 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.
After compatriot Demba Ba was left out of the squad because of his prospected move to European champions Chelsea in the January transfer window, he 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 and nine points above the relegation zone. 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.
Cissé also scored the first goal in a 3–1 loss away to Benfica in the first leg of Newcastle's Europa League quarter-final tie on 4 April. Three days later, he scored an injury time winner in a 1–0 victory over Fulham, causing him to jump into the crowd and sent manager Alan Pardew, in celebration, running in also. Cissé scored his fourth goal of the Europa League campaign in a 1–1 home draw with Benfica, but it was not enough to see Newcastle into the semi-finals of the competition as they fell 4–2 on aggregate.
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 game against Hull City on 20 September.
Cissé made his return from injury against Hull on 20 September, replacing Emmanuel Rivière in the second half, and scoring both goals for Newcastle as they came back from two goals down to rescue a 2–2 draw. Cissé celebrated both goals by lifting up his jersey to reveal a message dedicated to team-mate Jonás Gutiérrez, who recently revealed that he had been diagnosed with testicular cancer. Two weeks later, another brace by Cissé earned Newcastle an identical result at Swansea City. On 5 December, he came on as a substitute for Rémy Cabella and scored both of Newcastle's goals as they defeated leaders Chelsea 2–1, inflicting on their opponents a first defeat of the season. After scoring a penalty on Boxing Day in the 3–1 loss at Manchester United, Cissé scored again In the next game, scoring the equaliser in a 3–2 victory over Everton on December 28, taking his tally to nine league goals in just 14 matches. During the game, however, he intentionally thrust his elbow into Séamus Coleman's face during a corner. Cissé was charged with dangerous conduct and banned for three games by the FA. After returning from the 2015 Africa Cup of Nations, Cissé scored a header against Crystal Palace, his tenth league goal of the season, on 11 February. On 28 February, he scored his 11th goal of the season against Aston Villa with a goal just outside the six-yard box.
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 match ban 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 May 9.
Cissé started the first game 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 game 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, rumoured to be in the region of £2.5m. He scored on his second appearance for the club, in an eventual 4–1 win over Hangzhou Greentown.As of 30 October 2016
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. Cisse's most recent Senegalese goal was against Botswana in November 2014, his 16th international goal.EFFIFU Award: 2010–11
BBC Goal of the Month: May 2012
BBC Goal of the Season: 2011–12
Cissé is a practicing Muslim, and when celebrating a goal he often performs the Sujud. He has allegedly objected to Newcastle United's shirt-sponsorship deal with high-interest loans company Wonga due to apparently religiously-related moral reasons (Islam considers promoting usury or financial exploitation to be 'forbidden'). Following the publication of a photograph showing Cissé at a gaming table at Aspers Casino in Newcastle, it was announced that the matter had been resolved, with Cissé agreeing to wear the shirt featuring the logo of the loan company.
Cissé has been married twice; firstly to Adja Siny Thiaw (with whom he has a son, Ousmane) and secondly to volleyball player Diallo Awa. He was still married to Thiaw by the time he married Awa. Also, before he married Awa, he had affairs with three different British women.