The Mexico international continued his strong form in La Liga, scoring in the second half as his side fell at the Santiago Bernabeu.
With the Yellow Submarine trailing 3-1 in the 69th minute, Dos Santos curled a beautiful left-footed strike from 25 yards out that flew past a diving Diego Lopez and into the upper left corner of the net.
The goal wouldn't be enough for the visitors however, as a Karim Benzema double and goals from Gareth Bale and Jese Rodriguez helped secure the win for Los Blancos.
The strike was the 10th league goal of the year for the Mexican international, who has been in fine form recently as well, scoring three goals and adding four assists in his last five league matches.
Dos Santos played the full 90 minutes in the loss, as did his international teammate Javier Aquino. The pair met with Mexico national team boss Miguel Herrera earlier in the week, as El Piojo continued his tour of Europe.