At 04.01 hours on 3 July 1942, U-161 fired a spread of two stern torpedoes at the San Pablo, which laid berthed at the fully illuminated pier in Puerto Limón, Costa Rica and was discharging cargo. The ship was hit amidships and near the bridge in #1 and #2 holds and quickly settled to the bottom with only her superstructure above the water because the watertight doors between all holds had been left open. One crew member died on watch below and 23 stevedores (residents of Puerto Limon) working in the holds were killed. All but three crew members of the vessel were ashore at the time of the attack.

On 9 Jan 1943 the San Pablo was raised and after temporary repairs on 6 March, taken in tow by the tug Crusader to Tampa via Puerto Castilla and Key West, arriving on 28 March. It was first planned to repair the vessel, but she was declared a total loss and sunk as target 9 miles south-southeast of Pensacola Pass on 25 September.