The 32-year-old missed the whole of Barca's pre-season programme with a calf injury and was not part of their squad for their opening LaLiga loss to Athletic Bilbao last weekend.
Messi – whose last competitive outing was for Argentina in the Copa America third-place play-off victory over Chile, a match in which he was controversially sent off – returned to training on Wednesday, but Valverde is unsure whether he will be fit for the visit of Betis.
Speaking at his pre-match media conference, Valverde said: "If he is not 100 per cent, he will not play."
If Messi does feature, he will likely line up alongside Antoine Griezmann in attack.
The €120million signing from Atletico Madrid struggled to make an impact in last weekend's disappointing defeat, with Luis Suarez's first-half injury leaving him isolated up front.
Valverde says he is improving all the time and expects the France forward to start firing soon if he is given the right service.
"He is better every day," the Barca boss said. "He has to participate a lot and last week he did not participate as we would have liked.
"If he participates, he can be decisive, but we must help him."
Betis also opened their LaLiga campaign with a defeat last weekend – a 2-1 reverse to Real Valladolid – but Valverde is expecting a tough game at Camp Nou.
He added: "Betis are a team that have many options to allow them to be towards the top of the standings, but it is mandatory that we get all three points after losing last weekend."