The Argentine has seen his side go through a concerning period of form as the season reaches its climax, with just one victory in their last five matches.
Simeone shuffled his deck recently and opted to field a back three as Atletico played out an underwhelming 0-0 stalemate with Real Betis in La Liga.
Now the 47-year-old is weighing up the prospect of continuing with the new formation as his side prepare for the biggest game of their season.
‘My selection in London depends on what goes through my head on Wednesday, as well as my heart,’ Simeone said in the aftermath of the recent draw, as reported by FourFourTwo.
‘I may use three central defenders in London, why not?
‘The team is heading into Thursday’s game really well. We made important changes and the players responded, I had to rotate to ensure we had fresh players. That’s why I gave Vitolo, Fernando Torres, [Angel] Correa and Saul [Niguez] more minutes.
‘I expect everyone to have enough match fitness by Thursday.’
Arsenal could be handed a potential boost by Simeone’s decision to switch up his side, while also taking confidence from key man Diego Costa’s absence for the first leg.
Simeone confirmed recently that Costa has ‘no chance’ of being fit in time for the first-leg meeting, though is hopeful he will return in time for the reverse fixture.
Atletico last won the competition during the 2011-12 season, after beating fellow Spanish side Athletic Bilbao in the final in Bucharest.
Soon-to-be departing manager Arsene Wenger is yet to win a European trophy with the Gunners.