When World War II began, Puller was commanding the 1st Battalion, 7th Marine Regiment at New River (later renamed Camp Lejeune), North Carolina, and was sent with his unit to Guadalcanal in the summer of 1942. He won his third Navy Cross leading his battalion in defense of the island's Henderson Airfield against an overwhelming force of seasoned Japanese troops. Promoted to executive officer of the 7th Marine Regiment, Puller earned his fourth Navy Cross in January 1944 at Cape Gloucester in New Guinea, when he braved enemy fire to inspire his men during a Japanese counterattack. He was then given command of the 1st Marine Regiment, which he led at the Battle of Peleliu in the Palau Islands in September and October 1944. He returned to the United States the following month to train recruits at Camp Lejeune, where he remained for the rest of the war.
At the outbreak of the Korean War, Puller received command of his old unit, the 1st Marine Regiment, and led them during the landing at Inchon in September 1950. He then earned his fifth Navy Cross at the Chosin Reservoir later that year by "attacking in a different direction" against ten Chinese divisions. The action also earned him a promotion to brigadier general in 1951 and major general in 1953. In 1954, he assumed command of the 2nd Marine Division at Camp Lejeune but was forced to retire a year later because of ill health. He requested a return to service in 1966 to fight in Vietnam but was refused because of his age. His son, Lewis Burwell Puller Jr., also served as a Marine officer, losing both legs and parts of his hands in action in South Vietnam in 1968. His autobiography, Fortunate Son, won a Pulitzer Prize in 1992. The younger Puller killed himself two years later.
Lewis B. "Chesty" Puller died on October 11, 1971, at the age of seventy-three. He was buried in Saluda, in Middlesex County, where he spent his retirement. A Virginia Historical Highway Marker honoring him is located nearby on State Route 33, the "General Puller Highway."