Atletico experienced a summer of considerable change, with key players such as Rodri Hernandez, Diego Godin and Juanfran moving on while eight new faces arrived, including the £113.4m rated Joao Felix from Benfica.
Such overwhelming evolution flies in the face of what we know about Simeone's Atletico, which comprises of a core group of veterans whose key qualities revolve around indefatigability and impeccable organisation.
These principles continue to stand, but the Argentine boss is struggling to find a formula which gets the very best out of this current group of players.
Indeed, while Atletico's defensive record remains impressive - they have conceded just four times in La Liga - their attacking potency has considerably faded.
A record of seven goals from just eight games, despite the influence of Felix, demonstrates that this new-look team, although possessing the same durability, has not fully discovered its potential going forward as of yet, which is why Simeone reportedly wants to target Edinson Cavani in January.
Valencia can claim to have also experienced fundamental change over the summer through the surprise sacking of Marcelino, who was replaced by Albert Celades in early September.
Despite qualifying for the Champions League in consecutive seasons and winning the Copa del Rey in May, the popular Marcelino was removed amid disagreements with the club's ownership, leaving Valencia players with the task of starting all over again under their new manager.
Valencia's performances have not suffered, however, with Los Che unbeaten in four La Liga games alongside claiming an impressive 1-0 win at Stamford Bridge since Celades took charge.
Regardless of who sits in the dugout, Valencia boast an impressive core group of talents - the talismanic Rodrigo leading the line, Geoffrey Kondogbia and Dani Parejo patrolling the midfield, Ezequiel Garay and Gabriel Paulista forming a solid partnership at the back - who are capable of beating the best in Europe on their day.
However, Valencia's last away win at Atletico came in 2011 and they only have one success away from home in La Liga so far this season, meaning that the odds are stacked against the Andalusian side as they prepare to face Simeone's men.
Recent Atletico Madrid form: DDWDWD
Recent Valencia form: WDDWLW
Full-back Sime Vrsaljko has been sidelined since the start of the year with knee ligament damage and will miss Saturday's encounter, although the Croat is expected back next month.
Valencia have a few more injuries to worry about - especially when it comes to midfield duo Carlos Soler and Kondogbia, with the former set to be out for some time.
Atletico Madrid possible starting lineup:
Oblak; Trippier, Jimenez, Savic, Lodi; Saul, Partey, Koke, Felix; Morata, Costa
Valencia possible starting lineup:
Cillessen; Wass, Garay, Gabriel, Costa; Coquelin, Parejo, Cheryshev, Guedes; Rodrigo, Gomez
We say: Atletico Madrid 2-1 Valencia
Beating a Simeone side away from home is one of the hardest challenges in the game, and despite the attacking potential Valencia have on offer, their away record, combined with Atletico perhaps feeling like they have a point to prove going forward, means that the hosts are likely to get the better of this contest.