In the summer of 2016, at age 18, he was promoted from Olympiacos’ youth team by first manager Víctor Sánchez, who was impressed by his stamina. On 25 August 2016 he made his debut with the club in a Europa League play offs home match against Arouca.

On 8 February 2017, Retsos has appointed captain of the club in a Greek Cup goalless home draw against Atromitos. Retsos became the youngest captain of a Greek champion club aged only 18, five months and 30 days.

On 30 August 2017, the 19-year-old Retsos was sold to Bayer Leverkusen for a fee of £15.75 million. The Bundesliga outfit believe they have signed themselves a future star, with the teenager having already broken records in his career. The 19-year-old centre-back has signed a five-year deal with the Bundesliga outfit after Leverkusen beat off competition from Ligue 1 sides Stade Rennes and Lyon for his signature. On 17 September 2017, he made his debut in Bundesliga in a 4–0 home win game against SC Freiburg as a starter. On the club’s Twitter account, Retsos was voted the Man of the Match.

He made his debut for Greece on 31 August 2017, in a 0–0 home draw against Estonia in 2018 FIFA World Cup qualification.

On 9 April 2018, substitute Retsos scored his first goal in Bundesliga by firing into the far corner after a left-wing free-kick broke to him at the far post, in a 4–1 away win against RB Leipzig. It was his first goal in his professional career. In the Bundesliga this season, Retsos has made a total of 14 starts so far and has also made six substitute appearances. He has impressed during this time, displaying composure at the back for the German outfit.

On 2 August 2018, Retsos suffered a heavy blow to the quadriceps during pre-season training with Bayer Leverkusen and according to the initial medical evaluation, he was diagnosed with tendonitis in the right thigh. The injury is expected to sideline the defender for at least six weeks. It is Retsos’ first serious injury with the German club and he will miss the kick-off of the 2018–19 Bundesliga season. On 26 October 2018, Retsos is available for selection again and was on the Bayer Leverkusen bench in a UEFA Europa League match against FC Zurich.

On 29 November 2018, after a very difficult period for the defender marred by injury (208 days to be exact), Retsos returned to action in a UEFA Europa League home game against Ludogorets, but was unlucky as in the first half hour left the pitch with a muscular injury on his left thigh and according to the initial reports, Retsos will now spend another 10-12 weeks on the sidelines. On 29 October 2019, after a second very difficult period for the defender marred by injury (334 days to be exact), played in a DFB-Pokal game as a substitute in a 1–0 home win against Padeborn.

On 1 February 2020, Retsos signed for Premier League club Sheffield United on loan from Bayer Leverkusen until the end of the 2019–20 season.

On 4 October 2020, Bayer Leverkusen’s agreement with Saint-Étienne for the loan of Panagiotis Retsos to the French club has been completed with a purchase option of €6.5 million for the summer of 2021. The Germans will keep a 15% resale value and the 22-year-old centre-back is even expected to travel to France in the next few hours to complete his permanent transfer to the French club.