Despite rumors linking him to a possible move to Atlanta United and Los Angeles FC of the Major League Soccer, it was announced on 27 July 2017 that Spanish club Real Betis had signed Guardado for a reported €2.3 million on a three-year deal. The following month he was named their co-captain, and on 20 August he made his competitive debut, playing all 90 minutes in a 2–0 loss to Barcelona. He scored his first goal on 25 November, in a 2–2 home draw against Girona FC.