Later in the 1863, yellow fever broke out on board Arizona, forcing her back to New Orleans until the ship's company had returned to good health. During the month of November, she had made trips to Calcasieu Pass, Vermilion Bay, and Mermentau Lake on convoy and transport trips, and on 10 December, she transported Capt. John B. Marchand to Forts St. Philip and Jackson to investigate a mutiny. In December 1863, she went to Berwick Bay and, when the rise of water permitted, entered Grand Lake and the Atchafalaya and remained there on constant blockade. In February 1864, she went to New Orleans and, when repaired, returned to Sabine Pass for blockade duty—one of 14 vessels under Capt. March. That duty lasted until September 1864 when she proceeded to New Orleans for repairs. There, she was fitted out for service as the flagship of the West Gulf Blockading Squadron. In January 1865, Lt. Comdr. George Brown took command of the ship.

On the evening of 27 February 1865, while underway from Southwest Pass to New Orleans, 38 miles below New Orleans, a fire broke out in the engineer's after storeroom and spread with great rapidity. Brown ordered the magazine flooded and, when no possibility of saving the ship remained, ordered the crew to the boats. Some leaped overboard and swam to shore. The vessel drifted to the west bank of the river, grounded, and burned until she exploded 35 minutes past midnight. Out of a crew of 98 on board four were missing.