Mané made his professional debut for Metz on 14 January 2012, coming on as a substitute for Kévin Diaz in the 75th minute of a 0–1 home defeat against Bastia in Ligue 2. He made 19 appearances in his first league season, 12 as a starter, and scored a solitary goal in a 2–5 loss to Guingamp at the Stade Saint-Symphorien on 4 May. Metz were relegated to the Championnat National at the end of the season.

On 31 August 2012, Mané moved to Austrian Bundesliga side Red Bull Salzburg for the third biggest transfer fee that FC Metz had ever received. The fee was believed to be €4 million.

On 27 October 2013, he netted his first hat-trick in the Austrian Bundesliga, during a 3–0 win away to Grödig. He scored another treble on 7 May 2014 as Salzburg won 7–0 at Horn in the cup semi-finals; the season ended with the team winning a domestic double. At the end of August 2014 Mané forced a transfer out of the club, by not coming to the training and to the most important game for Salzburg at that time to qualify for the Champions League.

On 1 September 2014, Mané transferred to Premier League side Southampton for £11.8 million, signing a four-year contract. He made his debut 22 days later in a 2–1 League Cup victory over Arsenal, winning the penalty for Southampton’s first goal. He made his first league appearance for the club in another 2–1 victory over Queens Park Rangers on 27 September, starting and assisting Ryan Bertrand for the first goal of the game. He scored his first goal for the club in an 8–0 victory over Sunderland on 18 October, although this was subsequently credited as an own goal by Patrick van Aanholt. He did, however, score his first goal in his next game, a 1–0 win over Stoke City a week later.

In December and January he scored in three successive matches, against Crystal Palace, Chelsea and Arsenal. Mané scored two late winning goals in 1–0 league victories at Queens Park Rangers on 7 February 2015 and at home to Crystal Palace on 3 March respectively. However, Mané had been dropped from Southampton’s starting line-up for their 0–2 home defeat to Liverpool on 22 February as a punishment for being late to the stadium.

Mané was ruled out of the Senegalese squad for the 2015 Africa Cup of Nations after suffering a calf injury in Southampton’s 2–0 win against Arsenal on 1 January 2015. He later returned to the squad, and started in their final two group matches against South Africa and Algeria in a group stage exit.

On 2 January 2016, he was again dropped from the starting line-up by manager Ronald Koeman for a match at Norwich City when he turned up late for a pre-match meeting. He received a straight red card on 12 March at the end of a 2–1 win at Stoke City for a collision into Erik Pieters, although this was quickly overturned on appeal.

Having failed to score in the league for over four months, Mané scored twice in a 3–2 victory over Liverpool on 20 March 2016, followed by five goals in the next five matches, including a hat-trick in a 4–2 victory against Manchester City on 1 May. He finished the season as Southampton’s top scorer, with 15 goals in all competitions.

On 28 June 2016, Mané joined Liverpool for a transfer fee of £34 million on a five-year contract. The transfer fee made him the most expensive African player in history at the time. On 14 August, he made his Premier League debut for the Reds, scoring the fourth goal in a 4–3 away win against Arsenal. Having missed Liverpool’s defeat at Burnley through a slight shoulder injury, Mané returned to the starting line-up against Burton Albion in the League Cup where he had two assists in a 5–0 win.

On 19 December, Mané scored the only goal of the 227th Merseyside derby in added time against Everton at Goodison Park. On 11 February 2017, Mané scored two goals within two minutes against Tottenham Hotspur at Anfield, for Liverpool’s first league win in 2017. On 20 April 2017, Mané was named in the PFA Team of the Year after scoring 13 league goals in his first season with Liverpool. Despite missing the latter part of the campaign through injury, Mané was awarded the Liverpool Player of the Season award on 9 May 2017.

In the first match of the new season, on 12 August 2017, away to Watford, Mané scored Liverpool’s first goal of the season in a 3–3 draw. He was named Premier League Player of the Month after scoring a goal in each of the Reds’ three matches in August. On 9 September 2017, he was given a straight red card in the first half of a 5–0 loss to Manchester City for a high boot against goalkeeper Ederson, resulting in a three-match ban. Mané, Mohamed Salah, Roberto Firmino and Philippe Coutinho made up a prolific attacking quartet dubbed the “Fab Four” and “Fab Three” after the mid-season exit of the latter.

Mané pursued a career in football despite his father forbidding him from playing the sport as a child. He currently resides in Allerton and has been burgled twice, once in November 2017 and again in February 2019. He is a practising Muslim and occasionally is seen making du’a before the start of each match.

On 14 February 2018, Mané scored his first hat-trick for Liverpool in a 5–0 away win against Porto in the round of 16 first leg of the 2017–18 UEFA Champions League. In doing so, he became only the second player to score an away hat-trick for the club in Europe. Later, with a goal in the 3–0 win over AFC Bournemouth on 14 April, he overtook Demba Ba’s record of 43 to become the highest scoring Senegalese in Premier League history.

On 22 November 2018, Mané signed new long-term deal with the Reds. On 10 March 2019, Mané scored twice in a 4–2 win over Burnley, the second of which was his 50th competitive goal for Liverpool. His goals also saw him become only the fifth Liverpool player to score in six consecutive home Premier League appearances after Michael Owen, Fernando Torres, Luis Suárez and Salah. Three days later, he scored twice more in a 3–1 win over Bayern Munich to help Liverpool progress to the quarter-finals of the Champions League. In doing so, he became the club’s record goalscorer away from home in the competition with seven goals to his name. During Liverpool’s next match, he broke another of Ba’s records to become the Senegalese player with the most goals scored in a single Premier League season, after scoring his 17th goal for the campaign in a 2–1 win over Fulham. On 20 April, he was one of six players nominated for the PFA Players’ Player of the Year award alongside teammate Virgil van Dijk. He was also named in the PFA Team of the Year alongside Liverpool teammates, Trent Alexander-Arnold, Andrew Robertson and Van Dijk.

In May 2018, Mané was named in Senegal’s 23-man squad for the 2018 FIFA World Cup in Russia. He scored the opening goal in a 2–2 draw against Japan in the group stage. Mané started all three of Senegal’s group matches as they were eliminated after the first stage, finishing below Japan on fair play points.

On the final day of the domestic campaign, Mané scored twice in a 2–0 win over Wolverhampton Wanderers. His brace took him to 22 goals for the campaign which saw him share the Premier League Golden Boot award with Salah and Arsenal’s Pierre-Emerick Aubameyang. On 1 June, Mané helped win an early penalty for Liverpool in the 2019 UEFA Champions League Final against Tottenham, only 24 seconds after the kick-off, after his cross was judged to have hit Moussa Sissoko’s arm inside the penalty area; Salah subsequently converted from the spot to open the scoring, and Liverpool ultimately won the match 2–0 to claim the title.

On 14 August 2019, Mané scored twice in the 2019 UEFA Super Cup final against Chelsea in a match that Liverpool won 5–4 on penalties after the game had finished 2–2 after 120 minutes. Mané was named man of the match. Exactly one month later, he scored twice in a 3–1 win over Newcastle United and extended his record run of matches without defeat for Liverpool at Anfield to 50 matches, a league record by any player at a particular stadium. On his 100th Premier League appearance for Liverpool on 5 October, Mané scored his 50th league goal for the club in a 2–1 win over Leicester City.

On 7 January 2020, Mané was named the CAF African Footballer of the Year. He is only the second Senegalese after El Hadji Diouf to have won this award.

On 20 September 2020, Mané opened his scoring account in the 2020–21 Premier League with both Liverpool goals in a 2–0 win away to Chelsea. On 2 October 2020, Mané tested positive for COVID-19.