Atlético Madrid B
Simeone made his senior debut with Atleti's B-team on 17 January 2021, starting and scoring the opener in a 1–1 Segunda División B away draw against UD Poblense. He scored three further goals in the season, but his team suffered relegation.
After spending the 2021 pre-season with the first team, Simeone returned to the B's now in Tercera División RFEF, scoring eight goals in 11 matches between the months of November and December.
He debuted with the senior Atlético Madrid side in a 0–0 La Liga tie with Granada on 20 April 2022, coming on as a sub in the 91st minute.
Loans to Real Zaragoza and Alavés
On 4 July 2022, Simeone was loaned to Segunda División side Real Zaragoza for the season. He scored his first professional goal two months later, netting the opener in a 2–1 home loss against CD Lugo.
On 21 July 2023, Simeone renewed his contract with Atleti until 2028, and subsequently moved on loan to Deportivo Alavés in the top tier, for one year. On 6 August, during a pre-season friendly against Burgos CF, he broke his fibula and also suffered an ankle injury after a tackle from José Joaquín Matos.
Return to Atlético Madrid
In July 2024, Simeone returned to his parent club, Atlético Madrid, ahead of the 2024–25 season. On 3 November, he scored his first goal for the club in a 2–0 win over Las Palmas. On 29 January 2025, he scored his first UEFA Champions League goal and provided an assist in a 4–1 away win over RB Salzburg.
On 15 January 2026, Simeone extended his contract with Atlético Madrid until 30 June 2030.