Ramos missed Saturday's 2-0 home win against Espanyol with a hip injury sustained in last week's 3-1 home win over Napoli in the last 16 of the Champions League. However, he trained on Monday.
Real have an opportunity to keep the pressure on Barcelona, whom they lead by a point at the top of La Liga. Real will also have a make-up game to play against Celta Vigo.
Real coach Zinedine Zidane has used 19 players in the last two games and will continue his rotation policy, with a game at Villarreal to follow on Sunday.
Karim Benzema, Luka Modric and Keylor Navas all rested against Espanyol as part of seven changes made by Zidane to the side that beat Napoli, and all are set to start at the Mestalla stadium.
"We have a lot of games ahead and we need all the players," Zidane told his club's website after Saturday's win.
Gareth Bale could start too after impressing on his return from an ankle injury. The Welsh forward came off the bench and outpaced Espanyol's defence before scoring Real's second.
"He doesn't give the impression that he's been three months out," Zidane said. "He has a lot of power, makes a difference and that is why he is special."
The Valencia match was originally scheduled for December but was moved due to Real's involvement in the FIFA Club World Cup, which they won. Zidane wants his team to pull away from defending champions Barcelona as soon as possible.
"Only two teams can get points on Wednesday and this is important," he said.
While Real set a club record at the weekend by scoring in 42 consecutive games in all competitions, Valencia kept a clean sheet for a second straight game, while also ending their 262-minute goal drought thanks to Nani.
Valencia have slipped into relegation danger after enduring a season of frustration, but the players have a new spring in their step after Sunday's 2-0 home victory over Athletic Bilbao, a result that ended a three-game winless streak and lifted the team to 15th place.
(Reporting by Adriana Garcia; Editing by Mark Trevelyan)
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