Valencia’s Kevin Gameiro grabbed a stoppage-time equalizer after Denis Cheryshev had reduced the deficit with 20 minutes remaining, leaving the tie in the balance heading into the second leg at the Mestalla stadium on Feb. 28.
However, Real Betis striker Loren Moron headed Betis in front at the end of the first half while Joaquin doubled their advantage in early second.
A corner crossed the line before Valencia’s goalkeeper Jaume Domenech could pat it away, with the referee awarding the goal after consulting the Video Assistant Referee (VAR).
Betis, last lifted the trophy in 2005, and will be in pole position to reach the final in May.
Cheryshev almost levelled in the closing stages with a second header but instead struck the crossbar, but French striker Gameiro completed the comeback with a strike in added time.
The come back gives Valencia a huge psychological edge heading into the second leg, knowing that a goalless or a 1-1 draw will be enough for them to reach the final.
Meanwhile Barcelona played a 1-1 draw at home against Real Madrid in the first leg of the other semi-final tie on Wednesday.