After major repairs and an overhaul, Indianapolis received orders to proceed to Tinian island, carrying parts and the enriched uranium (about half of the world's supply of Uranium-235 at the time) for the atomic bomb Little Boy, which would later be dropped on Hiroshima. Indianapolis departed San Francisco on 16 July 1945, within hours of the Trinity test. Arriving at Pearl Harbor on 19 July, she raced on unaccompanied, delivering the atomic weapon components to Tinian on 26 July.
Indianapolis was then sent to Guam where a number of the crew who had completed their tours of duty were replaced by other sailors. Leaving Guam on 28 July, she began sailing toward Leyte where her crew was to receive training before continuing on to Okinawa to join Vice Admiral Jesse B. Oldendorf's Task Force 95.
At 00:14 on 30 July, she was struck on her starboard bow by two Type 95 torpedoes from the Japanese submarine I-58, under the command of Mochitsura Hashimoto. The explosions caused massive damage. The Indianapolis took on a heavy list, and settled by the bow. Twelve minutes later, she rolled completely over, then her stern rose into the air, and she plunged down. Some 300 of the 1,196 crewmen went down with the ship. With few lifeboats and many without lifejackets, the remainder of the crew were set adrift.