There are calls for Barcelona to sack coach Ernesto Valverde after promoted Granada stunned the champions to move top of La Liga.
Nigerian international Ramon Azeez headed in at the back post with less than two minutes played to set the tone for a disastrous night for the Catalans.
Valverde introduced Lionel Messi and Ansu Fati at half-time, but Alvaro Vadillo added the hosts’ second from the penalty spot after Arturo Vidal handled in the area.
The result condemns Barcelona to their worst league start for 25 years and leaves them in seventh, three points behind surprise leaders Granada.
Earlier, Atletico Madrid missed the chance to go top as they were held to a goalless draw against Celta Vigo.
Valverde made four changes to the side that unconvincingly drew 0-0 with Borussia Dortmund in the Champions League on Tuesday, as a returning Messi started on the bench once more.
But summer signing Junior Firpo – handed a first start after Jordi Alba picked up an injury in midweek – made a defensive slip that led to Granada taking the lead after just one minute and five seconds.
The early advantage proved no fluke, as the hosts pressed on and could have added to their advantage before the interval.
Barcelona’s best opportunity fell to Luis Suarez in first-half stoppage time, but the Uruguay forward’s goal-bound attempt was blocked on the line.
Messi and 16-year-old superstar Fati saw plenty of the ball in the second half, but despite their best efforts, neither could achieve a breakthrough before fellow substitute Vidal’s costly error allowed Vadillo to sweep home from the penalty spot.
The visitors never looked like getting back into the contest after that, as a resilient, dogged Granada recorded a famous victory.
Barca have now gone eight straight games without victory on the road, and the manner of Saturday’s reverse has prompted calls for Valverde to be sacked.
The Basque managed to hang on to the job after last season’s disastrous collapse at Liverpool. And now his position has become increasingly untenable as fans frown at the style of play and poor results.