San Luis is most famous for serving in the Falklands War (Guerra de las Malvinas/Guerra del Atlántico Sur) of 1982. Only one other submarine, the old Second World War era ARA Santa Fe was also operational at this time. After the Santa Fe was captured badly damaged and scuttled by the British in South Georgia on April 28, and the nuclear submarine HMS Conqueror had sunk the ARA General Belgrano on May 2, the Argentine fleet retired to port for the duration of the war, with the exception of the San Luis, making her the only Argentine naval presence facing the British fleet. The San Luis was a major concern for the British as she presented a serious danger.
San Luis reported two attacks on Royal Navy ships during the war. On May 1, the ships HMS Brilliant and Yarmouth were sent to hunt down the San Luis operating north of Stanley. San Luis reported firing one German-made SST-4 torpedo at the ship which subsequently missed.
San Luis attacked again on the night of May 10. Alacrity had made passage up Falkland Sound, sinking an Argentine merchant navy ship on the way. As Alacrity left the channel before dawn, its sister ship Arrow was waiting to escort her back to the Task Force. San Luis detected the two ships and fired two SST-4 torpedoes upon them. But the first torpedo didn't leave its tube and the second one was fooled by the Arrow's torpedo decoy.
San Luis returned to Puerto Belgrano on May 17 in an attempt to fix her weapons system but the war ended before she could sail again.