Goals either side of halftime from defender Curro Torres and rugged midfielder Ruben Baraja gave Valencia a deserved victory and put them firmly in the driving seat as the title race reaches its climax.
With three games to go Rafa Benitez's side lead the table on 75 points, followed by champions Real Madrid, who slumped to their second successive defeat on Saturday when they lost 2-0 at Deportivo Coruna, on 71.
Third-placed Barcelona have the chance to move to within a point of Real when they host city rivals Espanyol in Sunday's late match.
Fifth-placed Athletic Bilbao remained on course for a place in next season's UEFA Cup despite losing 2-0 at Sevilla, and Atletico Madrid moved up to sixth after a breathless 3-2 win at home to relegation-threatened Celta Vigo on Saturday.
The fight for survival remains as intense as ever but Albacete and Real Mallorca went a long way to assuring their future in the top flight with important home wins.
Albacete beat fellow strugglers Real Zaragoza 3-1, while Mallorca owed their 2-1 victory over Malaga to a double from newly crowned African Player of the Year Samuel Eto'o.
The surprise result of the day came when relegated Murcia gained only their fourth victory of the season with a 2-1 win at home to Valladolid, who sacked coach Fernando Vazquez at the start of the week.
INTENSE PRESSURE
Knowing that a win would put them four points clear of Real, Valencia subjected the visitors to intense pressure in midfield and gave them little time on the ball.
Betis had an early chance when Brazilian midfielder Marcos Assuncao skimmed the post with a 30-metre free kick, but otherwise Valencia laid siege to their opponents' goal for most of the first half.
Betis defender Washington Tais somehow managed to keep out a goal-bound header from Mista in the 16th minute and keeper Toni Prats pulled off a fine reflex save to deny the Valencia striker once again.
But Betis were unable to hold out, finally giving way nine minutes before the break after a defensive mix-up.
Baraja hooked a pass towards the Betis area, Denilson failed to clear and the ball fell to Curro Torres who toe-poked past Prats to put his side into the lead.
The home side made sure of the win early in the second half when Baraja curled the ball into the net from the edge of the area after substitute Pablo Aimar had raced clear on the right and cut back a neat pass.
Valencia, who play regional rivals Villarreal in the second leg of a UEFA Cup semi-final on Thursday, had several chances to extend their lead but it mattered little to the 51,000 fans inside the Mestalla who were left celebrating a win that makes them firm favourites to win the title.
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