The visitors were dealt a blow after 20 minutes when Lionel Messi had to be withdrawn with a hamstring problem, but it did little to disrupt Gerardo Martino's side, who went into the break two goals to the good.
Neymar claimed the first 10 minutes before the interval, tapping home after being set up by Cesc Fabregas, before Pedro ran from his own half to finish in fine style a minute later.
Fabregas found the net with a simple finish on 63 minutes, before netting his second 11 minutes from time with a header from Dani Alves' cross.
Alves then brought down Javier Matilla inside the box in stoppage time, Jorge Molina sending Victor Valdes the wrong way from the spot to spoil the leaders' clean sheet.
Diego Simeone's side got off to a dream start when Mario Gaspar put through his own net in the third minute, but the hosts replied through another own goal, Juanfran deflecting the ball into his own net with 11 minutes remaining.
It brought to an end Atletico's run of three consecutive victories as they lost ground on the leaders.
Valencia's troubled start to the season continued as they twice had to come from behind to earn a 2-2 at home with struggling Real Valladolid.
