Barcelona hold an eight-point lead over second-placed Atletico, which would be reduced to five if the visitors can win at the Nou Camp.
Atletico, however, have never beaten the Catalans in the top flight since Simeone took charge in December 2011.
"That we've never won at the Nou Camp (actually) makes me very optimistic," Simeone told reporters on Friday.
After Atletico were knocked out of the Champions League by Juventus in the last 16, their hopes of glory this season are pinned on winning La Liga.