Betis add to Atletico troubles
Although Atletico had the greater possession, Betis goalkeeper Espinosa Casto was rarely called upon as the visitors moved level on points with their hosts, whose coach Manzano has found himself under pressure following an inconsistent start to the season.
Betis, who had lost ten of their previous 12 competitive matches but defeated high-flying Valencia last weekend, took the lead through Pozuelo in the 54th minute, with Santa Cruz sealing victory in the final minute as Atletico suffered their first league home defeat of the season.
Atletico had the first real chance of the game after five minutes but Radamel Falcao put his shot from the six-yard box wide.
It took Betis until the 20th minute to have a shot on target when Santos Iriney's 20-yard effort was comfortably held by Thibaus Courtois. Benat Etxebarria hit a free-kick wide from the right for the visitors but neither side was threatening the goal.
Diego then came closest to the breakthrough in the 38th minute when Casto failed to hold his shot from the left side of the area, the ball going for a corner from which nothing materialised.
Atletico were clearly on top and they almost took the lead a minute before half-time when Arda Turan's volley was tipped round the post by Casto, but the break came with the game goalless.
Pozuelo opens the scoring
Atletico were more prominent at the start of the second half but it was the visitors who took a surprise lead in the 54th minute. Ruben Castro played a ball from the left side of the area which found Pozuelo six yards out and the midfielder slotted home.
Diego Godin headed over from close range and Juanfran's cross was punched clear as the hosts responded. Time was beginning to count down, with the hosts failing to force the Betis goalkeeper into any serious work until Adrian's header brought a parry from Casto.
Adrian shot over from 20 yards as the game entered the last ten minutes. Eduardo Salvio headed wide and substitute Jose Antonio Reyes shot over from 25 yards as the hosts desperately sought an equaliser.
However, they were left undone as Betis claimed a second, and all three points, thanks to Santa Cruz in the last minute. The Paraguayan fired in a shot from the right which hit the bar but he was smart to react and drilled home into the top right-hand corner of the goal from the centre of the area.