Ayew spent the following two seasons on loan with Lorient and Arles-Avignon, helping the latter team earn promotion to Ligue 1 for the first time.

In 2010, he returned to Marseille and became an integral part of the first team under manager Didier Deschamps, making over 200 appearances and winning consecutive Trophée des Champions and Coupe de la Ligues in both 2010 and 2011.

After four years of plying his trade in the club's youth academy, he was promoted to the team's senior squad at the age of 14.

Ayew made his professional debut for Marseille on 15 August 2007 in a league match against Valenciennes, coming on as a substitute for Modeste M'bami in the 89th minute.

Ayew was used by manager Christian Gourcuff as one of the team's focal points of the attack alongside Fabrice Abriel, Kevin Gameiro and Rafik Saïfi and made his debut on 16 August 2008, coming on as a substitute in a 0–0 draw against Lyon.

Two months later, on 31 August 2009, the last day of the transfer window, new manager Didier Deschamps confirmed that Ayew would be joining newly promoted Ligue 2 club Arles-Avignon on loan for the 2009–10 season.

After the successful league campaign with Arles-Avignon, on 16 May 2010, Marseille manager Didier Deschamps confirmed that Ayew would be returning to the team and that he will be earning some significant playing time with the club for the 2010–11 season.

[27] Despite the arrival of Loïc Rémy, Ayew was inserted as a starter by Deschamps and scored his first goal in the second league match of the season against Valenciennes in a 3–2 defeat.

[29] In the Coupe de la Ligue, Ayew scored goals in victories over Guingamp and Monaco in the Round of 16 and quarter-finals, respectively.

[34] Ayew was named in the squad for the 2011 Trophée des Champions match against Lille held on 27 July 2011 at the Stade de Tanger in Morocco.

On 22 February 2012, Ayew scored a goal in the 93rd minute, in a 1–0 victory over Inter Milan in the 2011–12 UEFA Champions League round of 16 first leg.

[44] On 8 August 2016, Ayew signed for West Ham United for a then club record fee of £20.5 million on a three-year contract, with the option of an extra two years.

[45] Ayew's debut game for West Ham, on 15 August 2016, against Chelsea, lasted 35 minutes before he was substituted after sustaining a thigh injury.

[53] On 13 August 2019, Ayew made his first appearance for Swansea since 2018, scoring two goals in a 3–1 win against Northampton Town in the EFL Cup.

[58] On 21 July 2021, Qatar Stars League club Al Sadd SC announced that they had reached an agreement to sign Ayew on a free transfer.

[60][61][62] On 22 July, the club announced his transfer and unveiled him after he had signed a two-year contract with an option for an additional year.

[63] During his only full season at Al Sadd, Ayew finished as second-top goalscorer in the QSL as the team won its 16th league title.

[64] On 2 February 2023, following his release from Al Sadd, Ayew joined Premier League club Nottingham Forest on a contract until the end of the season.

[65] On 26 April, Ayew came on as late substitute in a 3–1 victory over Brighton & Hove Albion to make his 100th Premier League appearance.

At the African Youth Championship, Ayew scored two goals against Cameroon in the group stage and South Africa in the semi-finals.

Ayew then captained the team to victories over the South Korea and Hungary in the quarter-finals and semi-finals, respectively, to reach the final where they faced Brazil.

On 19 January 2010, in the team's final group stage match against Burkina Faso, he scored his first international goal in 30th minute with a header.

On 7 May 2010, Ayew was named to coach Milovan Rajevac's 30-man preliminary squad to participate in the 2010 FIFA World Cup.

On 12 June, Ayew made his FIFA World Cup debut in the team's opening group stage match against Serbia, starting ahead of the more experienced Sulley Muntari.

He went on to play in the 2012 Africa Cup of Nations, scoring against Mali and Tunisia, as the Black Stars finished in fourth place.

[82] He then went on to start in both legs of Ghana's 7–3 aggregate play-off defeat of Egypt to secure qualification to the 2014 FIFA World Cup.

[94] Following a 3–2 victory over South Korea,[95] Ghana required a win or draw in their final group match against Uruguay to advance, and were awarded an early penalty, taken by Ayew.

At half-time, Ayew and his brother Jordan were both substituted, but the scoreline finished unchanged at 2–0, to send Ghana home in fourth place in their group.

[96][97] He has been omitted from the Ghana Black star squad for the 2026 World Cup qualifier matches against Mali in Bamako and Central African Republic in Kumasi.

This was a move that was made to encourage and motivate the team ahead of the Africa games slated for the following month in Rabat, Morocco.