The Argentinian hit a treble on his last La Liga appearance for Madrid, away to Espanyol on October 2, and added another for his country in the World Cup qualifying match against Chile.
Higuain could not prevent Argentina stumbling to a 1-0 defeat against Venezuela on Tuesday, but he was back to full steam against Betis.
Jose Mourinho's team were subdued in the first half, carving out few notable chances, but Higuain set the tone after the interval when he scored inside the opening minute.
Marcelo released Cristiano Ronaldo along the left flank and the Portuguese winger accelerated clear of marker Chica before taking the unselfish option and playing a square pass for Higuain to tap in.
It was 2-0 in the 59th minute and again Ronaldo was involved on the left.
He teased the Betis defenders, drawing them close before picking out Kaka breaking into the penalty area.
The Brazilian took two touches to set himself before threading a right-footed shot into the right corner.
Betis began the season with four wins but have now followed that with three defeats.
They briefly troubled Madrid when Ruben Castro bundled his way into the penalty area and the ball fell to Jorge Molina, whose left-footed shot took a nick off Marcelo on its way past Iker Casillas.
That came in the 69th minute but a minute later it was 3-1 to the home side.
Substitute Angel Di Maria played a smart ball from the right for Higuain to collect and sidestep goalkeeper Espinosa Casto before sliding in a precise finish from a narrow angle.
The hat-trick arrived in the 73rd minute, with Di Maria again the creator.
He produced a burst of pace in midfield and played another precise pass through the Betis defence for Higuain, who saved his best finish for last, chipping the ball delicately over Casto.