Van der Vaart swapped Hamburg for Betis in June but fans have had a long wait to see the former Real Madrid star in action, with the Dutchman an unused substitute for the past two matches following an ankle injury.
The 32-year-old finally made his debut at Estadio Benito Villamarin in Seville on Thursday, though he was unable to prevent a second defeat of the season.
After a goalless opening half, Deportivo broke the deadlock via loanee Federico Cartabia in the 54th minute.
Cartabia - on loan from Valencia - scored a sensational long-range strike that caught goalkeeper Antonio Adan by surprise.
Deportivo's lead was short-lived after Real target Dani Ceballos teed up Petros, who side-footed the ball across German Lux five minutes later.
The visitors, however, had the final say as Faycal Fajr latched on to Celso Borges' header and volleyed past Adan with 18 minutes remaining.