Island Number Ten, a small island at the base of a tight double turn in the river, was held by the Confederates from the early days of the war. It was an excellent site to impede Union efforts to invade the South by the river, as ships had to approach the island bows on and then slow to make the turns. For the defenders, however, it had an innate weakness in that it depended on a single road for supplies and reinforcements. If an enemy force managed to cut that road, the garrison would be isolated and eventually be forced to surrender.

Union forces began the siege in March 1862, shortly after the Confederate Army abandoned their position at Columbus, Kentucky. The Union Army of the Mississippi under Brigadier General John Pope made the first probes, coming overland through Missouri and occupying the town of Point Pleasant, Missouri, almost directly west of the island and south of New Madrid. Two days after the fall of New Madrid, Union gunboats and mortar rafts sailed downstream to attack Island No. 10. Over the next three weeks, the island's defenders and forces in the nearby supporting batteries were subjected to a steady bombardment by the flotilla, mostly carried out by the mortars.

Pope persuaded Flag Officer Andrew Hull Foote to send a gunboat past the batteries, to assist him in crossing the river by keeping off any Southern gunboats and suppressing Confederate artillery fire at the point of attack. The USS Carondelet, under Commander Henry Walke, slipped past the island on the night of April 4, 1862. This was followed by the USS Pittsburg, under Lieutenant Egbert Thompson two nights later. With the support of these two gunboats, Pope was able to move his army across the river and trap the Confederates opposite the island, who by now were trying to retreat. Outnumbered at least three to one, the Confederates realized their situation was hopeless and decided to surrender. At about the same time, the garrison on the island surrendered to Flag Officer Foote and the Union flotilla.

The Union victory marked the first time the Confederate Army lost a position on the Mississippi River in battle. The river was now open to the Union Navy as far as Fort Pillow, a short distance above Memphis. Only three weeks later, New Orleans fell to a Union fleet led by David G. Farragut, and the Confederacy was in danger of being cut in two along the line of the river.