Atletico Madrid have now put Juanfran through an MRI scan and he has an injury to the hamstring on his left thigh.
Simeone rested forward Antoine Griezmann and midfielder Jorge "Koke" Resurreccion, before sending both on as second-half substitutes.
"It's normal", said Simeone. "But now comes the most handsome part, what we have been working all year for, and we will give it our all".
Betis otherwise looked comfortable throughout the opening 45 minutes, although their hopes of securing a sixth successive clean sheet appeared to suffer a setback when Gimenez limped off with an apparent thigh problem, the goalkeeper replaced by understudy Pedro Lopez.
Betis, meanwhile, consolidate their hold on fifth place after extending their unbeaten run to seven games.More news: Private funeral service for Barbara Bush on Saturday
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Atletico Madrid sit in second spot in La Liga with four games left to play, eleven points behind Barcelona and four ahead of city rivals Real Madrid. "We'll have to seize control of the match", he added. Barcelona won 5-0.
Elsewhere on Sunday, Las Palmas had their relegation from La Liga confirmed following an emphatic 4-0 defeat at home to Alaves. The Canary Islands club had spent three seasons in the top tier.
"The doctors will inform us but I think it won't be possible for him to be ready for this game", Simeone said. "We must all accept our measure of responsibility and the criticism we will receive".
Spanish media outlet AS claims that the Slovenia worldwide has a €100 million (£87.5 million) inserted into his current contract with Atleti, and he still has three years remaining on his deal in the Spanish capital.
Gerard Moreno scored two goals for Espanyol to give interim coach David Gallego a win on his debut.