HMS Carlisle was completed with a hanger positioned under the bridge, and she was to carry aircraft, however this proved unsatisfactory and was later removed. In 1919 Carlisle joined the 5th Light Cruiser Squadron at Harwich. During March she left Harwich in company with the squadron, and they were then stationed in China. In the period 1921-1929 Carlisle received a refit, and then served on the Africa Station with the 6th Cruiser Squadron. In February 1930, Carlisle was docked in the Selborne dry dock at Simonstown, South Africa prior to becoming a unit of the 2nd cruiser squadron Atlantic (home fleet). On 16 March 1937, after being relieved by the cruiser Neptune, Carlisle returned to the U.K. and was reduced to reserve. In June 1939 Carlisle started a coversion to an A/A cruiser 8-4" QF MK16 and 1 quadruple 2 pdr Pom-Pom being fitted. This conversion was completed in January 1940.

In April 1940 during the Norwegian campaign Carlisle was employed on escort duties of a troop convoy consisting of the 148th Infantry Brigade who went ashore at Andalsnes, with this the German position in Trondheim was threatened from the north and south (Operation Sickle). Later during the month the sloop HMS Bittern which was mistaken for a cruiser, was badly damaged by German JU88s and had to be sunk by Carlisle. In August Carlisle was serving in the Red Sea and Gulf of Aden area when she assisted in the evacuation of British troops, civilians and the sick from Berber in British Somali to Aden before being occupied by Italian troops.

In March 1941 she was in the Mediterranean and was deployed on escort duties as an A/A vessel of the 15th cruiser squadron for convoys from Alexandria to Greece (Operation "Lustre"). During April she assisted in the evacuation of troops from Greece to Crete and Egypt. By early May she was involved in convoy duties, later that month on the 22nd, Carlisle and HMS Calcutta reinforced Admiral King`s squadron to help with the destruction of a German invasion convoy to Crete. As soon as it was sighted the British ships opened fire. For a short time all went well, a schooner and a steamer were destroyed and an escorting destroyer damaged by shelling. This destroyer laid a very effective smoke screen which concealed what remained of the convoy and the action was broken off. The air attacks which Admiral King feared more than anything intensified and his squadron was under continual attack for over three hours. Carlisle received a direct hit which killed her Commanding Officer Capt. Thomas Cloud Hampton, RN). The British destroyer HMS Kingston immediately went alongside to give assistance, but the fire now raging and the still continuing air attacks prompted the cruiser`s Senior Officer to refuse the destroyer`s offer. Carlisle then continued to engage the enemy with a furious barrage. By December, the old cruiser was back performing convoy duties between Alexander and Malta, she was tasked to support the commissioned auxiliary supply ship HMS Breconshire (9776 tons).

On 20 March 1942, Carlisle was employed as convoy escort to the commissioned auxiliary supply ship HMS Breconshire loaded with 5,000 tons of precious fuel, the Clan Campbell, the bomb damaged ship of the previous convoy, the Pampas and the Norwegian ship Talabot, fully loaded with ammunition. Getting this convoy through to Malta was afterwards referred to as the second battle of Sirte. Admiral Vian was in command of the operation. Of the total of 26,000 tons of stores carried by the four ships only 5,000 tons finally reached Malta. The price paid for delivering much needed stores was indeed heavy.

In July 1943, she provided escort for the support force for the Allied landings in Sicily. During September-October, during the German counter attack in the Aegean, HMS Carlisle (Capt. Harold Fielding Nalder, RN) made a sortie into the area south of Piraeus with the destroyers HMS Panther and HMS Rockwood in order to intercept German convoys in the Scarpanto Strait. It was here that on 9 October 1943 they were spotted by German JU87's dive bombers which succeeded in sinking HMS Panther and later on seriously damaging Carlisle in position 35º48'N, 27º36'E so that she had to be taken in tow to Alexandria by Rockwood. On examination of the damage it was concluded that Carlisle was a constructive loss. She remained at Alexandria as a base ship for the remainder of the war.

HMS Carlisle is not listed as active unit in the October 1944 Navy List

In 1948 the old cruiser was finally broken up for scrap at Alexandria.

Her badge can still be seen painted on the side of the Selborne dry dock wall at Simonstown, South Africa.