After completion USS Blakeley (DD 150) joined the Atlantic Fleet and was decommissioned at the Philadelphia Navy Yard, Pennsylvania on 29 Jun 1922 and placed in reserve. From 1932 to 1937 reactivated for duty in the Scouting Fleet.
On 16 Oct 1939, the destroyer was recommissioned for the Neutrality Patrol and later served in the Caribbean.

From 1 Jan, to 23 Feb 1943, USS Blakeley (DD 150) served in the hunter-killer group TG 21.13 in the North Atlantic and was then again used for escort duty in the Caribbean. On 21 Jul 1945 decommissioned and sold for scrap.

USS Blakeley (DD 150) received one battle star for her convoy duty in WWII. 

On 22 May 1942, seven survivors in one boat from the Quaker City were picked up by USS Blakeley (DD 150) in 15°01N/57°38W and landed at Trinidad on 24 May.

At 15.52 hours on 25 May, the USS Blakeley (DD 150) was patrolling off Martinique in the French West Indies, when she was hit by a torpedo from U-156 which carried away 60 feet of her bow. The explosion killed six men and wounded 21, but the ship did not sink and reached Port de France, Martinique for emergency repairs.

After additional repaires in Port Castries, Santa Lucia and in San Juan, Puerto Rico the destroyer sailed to Philadelphia where she was refitted with the bow taken from her stricken sister ship USS Taylor (DD 94) and was thoroughly overhauled. She returned to duty in the Caribbean in September 1942.