Mourinho has only lost once since retaking charge in Madrid, but a trip to their city rivals is a different level of test, ahead of an October El Clasico date with Barcelona.
The veteran Portuguese boss won all four clashes with Atletico during his first season in Madrid, back in 2010/11, with two each in LaLiga and the Copa del Rey.
He then won 4-1 home and away in 2011/12 - with the latter his first clash with Simeone - before going on to win twice more in 2012/13, but defeat in the 2013 Copa del Rey final blocked him from completing a 100% Madrid derby record.
Real Madrid v Atletico team news
Mourinho rotated for the 3-2 win at Elche in midweek, and he confirmed no fresh injury worries, with Ferland Mendy, Rodrygo and Eder Militao all still out.
Denzel Dumfries is expected to come in for Trent Alexander-Arnold as Mourinho's preferred choice at right-back with Jude Bellingham promoted from the bench in place of Yan Diomande.
Simeone confirmed Julian Alvarez is fit to be involved, but the Argentina international is unlikely to start, as he hosts stay unchanged.
Real Madrid v Atletico predicted line ups
Real Madrid XI: Courtois; Dumfries, Konate, Huijsen, Cucurella; Valverde, Tchouameni, Bellingham; Guler, Vinicius Junior; Mbappe.
Atletico Madrid XI: Oblak; Llorente, Le Normand, Romero, Grimaldo; Cardoso, Koke, Baena; Kang-in Lee, David, Lookman.
Real Madrid v Atletico kick off time
Kick off at the Estadio Metropolitano is set for 4:15pm local time and 3:15pm in the UK.
Key stat
Mourinho will need to produce something special to break Atletico's strong recent home record against Real Madrid as Simeone's charges are unbeaten at the Metropolitano in their last five derby head-to-heads.