During the American Civil War, he commanded the Western Gunboat Flotilla, where he won an important engagement in the First Battle of Memphis before capturing enemy supplies on a successful expedition up the Yazoo River.

[5][6][page needed][7] Historian Donald L. Miller describes Davis during the time of the Civil War as "tall, solemn-looking and contemplative, with a drooping mustache that hung over his mouth.

On April 30, 1857, he mediated with the Central American forces at San Juan del Sur, Nicaragua, the capitulation of filibuster William Walker and some 300 men, who departed in the St. Mary's for Panama the next day.

In 1859, while commanding the St. Mary's, Davis was ordered to go to Baker Island to obtain samples of guano, becoming perhaps the first American to set foot there since it was annexed by the United States in 1857.

A day after he took command, the flotilla fought a short battle with Confederate ships on the Mississippi River at Plum Point Bend on May 10, 1862.

Afterwards, because of a severe outbreak of malaria among his crew which left his ships undermanned, he withdrew 160 miles north to Helena, Arkansas, which had recently been occupied by the Union Army.

After his removal from command of the gunboat flotilla in September – Secretary of the Navy Gideon Welles admired Davis and liked him personally, but said of him that he was "more of a scholar than [a] sailor... not an energetic, driving, fighting officer, such as is wanted for rough work on the Mississippi" – he was made Chief of the Navy's Bureau of Navigation and returned to Washington, D.C.. On February 7, 1863, he was promoted to rear admiral.

[18] Davis translated into English Carl Friedrich Gauss's Theory of the Motion of the Heavenly Bodies Moving about the Sun in Conic Sections (1809), which was published in 1857.

[19] After the Civil War, Davis joined the Military Order of the Loyal Legion of the United States (MOLLUS).