For twenty-six months after that awkward maiden voyage, Don Isidro and her older sister Don Esteban were celebrated as the finest vessels in Philippine inter-island passenger service. Then Pearl Harbor ended that world. On December 8, 1941 (Philippine time), Japan struck the Philippines within hours of striking Hawaii. By January 1942, Don Isidro had been placed under the War Shipping Administration and allocated to the U.S. Army under charter. She was loaded in Brisbane with rations and ammunition bound for the besieged forces on Bataan. The soldiers still holding out on that peninsula desperately needed what she was carrying. Whether they would ever receive it was another matter.

The mission to run the Japanese blockade of the Philippines was, from the start, entangled in confusion. Captain Rafael J. Cisneros took the ship south around Australia to Fremantle for engine repairs before heading north — a detour that attracted official criticism. Science fiction author L. Ron Hubbard, then a U.S. Navy lieutenant, was formally disciplined for his role in routing Don Isidro those extra three thousand miles. By the time she arrived at Batavia (Jakarta) on February 9 to receive final instructions, Singapore had nearly fallen. The Japanese were on Sumatra, Java was being isolated, and every original plan was dissolving. Cisneros joined a British convoy through the Sunda Strait and tried to thread south of Java, through the Timor Sea, and across to the Philippines via New Guinea and the Bismarck Sea. Singapore surrendered while he was en route. Bali fell. Java was cut off.

On February 17, an unknown destroyer and freighter were spotted heading in the opposite direction. The next day, a Japanese bomber attacked twice — doing no damage but convincing Cisneros to turn toward Darwin as a safe harbor. On the morning of February 19, seven Japanese fighters found Don Isidro about 25 miles north of Bathurst Island. They strafed her thoroughly: holes opened in her hull, every lifeboat and life raft was destroyed, crew and soldiers were wounded. An army detachment from the 453rd Ordnance Company — fifteen men who had won their assignment by a coin toss, now armed with five improvised .50-caliber machine gun mounts — returned fire until their weapons were silenced. In the early afternoon, a single bomber attacked again but missed.

Japanese aircraft returning from the Darwin strike had fuel and ammunition remaining. Nine dive bombers, rearmed and refueled from carriers Soryu and Hiryu with 250-kilogram bombs, found Don Isidro. With no lifeboats left, nowhere to escape to, and the ship already damaged, the result was decisive. The ship was hit, heavily damaged, and set ablaze. Cisneros tried to beach her near Bathurst Island but the engines failed three miles offshore. Survivors jumped into the water and swam for land. The process of reaching shore took approximately ten hours. Of the sixty-seven crew and sixteen soldiers aboard, eleven crew members and Second Lieutenant Joseph F. Kane — the officer who had won his command by coin toss — died. Kane succumbed to gangrene in hospital at Darwin. Posthumously, he and his entire detachment received Purple Hearts.

HMAS Warrnambool rescued survivors and brought them to Darwin, where they were treated at hospital and then billeted at the 147th Field Artillery camp. The wreck of Don Isidro rests near Melville Island and is protected under the Commonwealth Historic Shipwrecks Act 1976. Two relics — a silver salt dish and a platter — are held at the Museum and Art Gallery of the Northern Territory in Darwin. Don Isidro was one of eight ships that attempted to run the Japanese blockade of the Philippines from outside the islands. Only three succeeded. She did not. But her crew fought as long as they could, and the men who manned those improvised gun mounts kept firing until nothing was left to fire with.