Following an absence as a result of the hamstring injury, Guardado played his first match of the 2020–21 season against Valencia on 3 October, coming on as a stoppage time substitute in a 2–0 away league victory, marking it as his 14th season in Europe and becoming the Mexican with most seasons in Europe, surpassing Hugo Sánchez's record of 13. On 17 January 2021, after recovering for nearly two weeks from COVID-19, Guardado returned to the field, coming on as a second-half substitute in the Copa del Rey round of 32 match against Sporting de Gijón, winning 2–0.