After the German invasion of June 1941, Malenkov was promoted to the State Defense Committee (GKO), along with Beria, Voroshilov and Molotov with Stalin as the committee's head. This small group held immense power and Malenkov's membership thus made him one of the most powerful men of the Soviet Union. During 1941 – 1943 Malenkov's primary responsibility in the GKO was aircraft production. In 1943 he became a chairman of a committee that oversaw the economic rehabilitation of liberated areas.

In 1946 Malenkov was named a candidate member of the Politburo. Although Malenkov fell out of favour in place of his rivals Andrei Zhdanov and Lavrentiy Beria, he soon came back into Joseph Stalin's favour, especially after Zhdanov's death. Beria soon joined Malenkov, and both of them saw all of Zhdanov's allies purged from the Party and sent to labour camps. In 1948, Malenkov became a Secretary of the Central Committee. In order to test Malenkov as a potential successor, the ageing Stalin increasingly withdrew from the business of the secretariat, leaving the task of supervising the body to Malenkov. In October 1952, Stalin even had the office of General Secretary formally abolished (though in effect this did not diminish Stalin's authority).

Malenkov's ambitions seemed to fulfill themselves upon Stalin's death on 5 March 1953. He was considered the most important member of the Secretariat and, with Beria's support, Malenkov became Premier of the Soviet Union. However, on 13 March he had to resign from the Secretariat due to the opposition of other members of the Politburo of the CPSU Central Committee. While Malenkov headed the government, Nikita Khrushchev, another of the secretaries, eventually assumed supreme leadership of the party as First Secretary of the CPSU in September 1953, ushering in a period of a Malenkov - Khrushchev duumvirate.

Malenkov retained the office of premier for two years. During these years, he was vocal about his opposition to nuclear armament, declaring "a nuclear war could lead to global destruction." He also advocated refocusing the economy on the production of consumer goods and away from heavy industry, something his successor Nikita Khrushchev (1955 – 1964) would escalate.

He was forced to resign, in February 1955, after he came under attack for his closeness to Beria (who was executed as a traitor in December 1953) and for the slow pace of reforms, particularly when it came to rehabilitating political prisoners. Malenkov remained in the Politburo's successor, the Presidium.

Together with Khrushchev, he flew to the island of Brioni (Yugoslavia) on the night of 1 – 2 November 1956 to inform Josip Broz Tito of the impending (bloody) Soviet invasion of Hungary scheduled for November 4.

However, in 1957, he was again forced to resign due to participation in a failed attempt together with Nikolai Bulganin, Vyacheslav Molotov, and Lazar Kaganovich (the so called Anti - Party Group) to depose Khrushchev. In 1961, he was expelled from the Communist Party and exiled within the Soviet Union. He became a manager of a hydroelectric plant in Ust' - Kamenogorsk, Kazakhstan.

Simon Sebag Montefiore says in his 2003 Stalin: Court of the Red Tsar that Malenkov found this demotion actually a pleasant relief from the pressures of the Politburo. Furthermore, Sebag Montefiore reports, Malenkov in his later years became a devout Christian, as did his daughter, who has since spent part of her personal wealth building churches throughout the former Soviet Union. Orthodox Church publications at the time of Malenkov's death said he had been a reader (the lowest level of clergy) and a choir singer in his final years.

When, in 1954, a delegation of the United Kingdom's Labour Party (including former Prime Minister Clement Attlee and former Secretary of State for Health Aneurin Bevan) passed through Moscow on their way to the People's Republic of China, Sir William Goodenough Hayter, British Ambassador to the Soviet Union, requested a dinner meeting with Nikita Khrushchev - then General Secretary of the Communist Party of the Soviet Union. Much to Hayter's surprise, not only did Khrushchev accept the proposal, but decided to attend in the company of Vyacheslav Molotov, Anastas Mikoyan, Andrey Vyshinsky, Nikolay Shvernik, and Georgy Malenkov. Such was the interest aroused in British political circles by this event that Sir Winston Churchill subsequently invited Sir William Hayter down to Chartwell so as to provide a full account of what had transpired at the meeting.

Malenkov seemed "easily the most intelligent and quickest to grasp what was being said" and said "no more than he wanted to say". He was considered an "extremely agreeable neighbour at the table" and was thought to have had a "pleasant, musical voice and spoke well educated Russian". Malenkov even recommended, quietly, that British diplomatic translator Cecil Parrott should read the novels of Leonid Andreyev - an author whose literature was at that moment in time, condemned as decadent in the USSR.

Nikita Khrushchev, by contrast, struck Hayter as being "rumbustious, impetuous, loquacious, free - wheeling, and alarmingly ignorant of foreign affairs". Hayter observed that he "spoke in short sentences, in an emphatic voice and with great conviction ..... grinning good naturedly", that he often "stumbled in his choice of words" and "said the wrong thing." Hayter thought that Khrushchev seemed "incapable of grasping Bevan's line of thought," and that Malenkov had to explain matters to him in "words of one syllable". Given to "interrupting," he (Khrushchev) seemed more eager to talk than to listen and to understand. He was "quick, but not intelligent". Convinced that Malenkov was in charge, nobody in the British delegation felt much inclined to expend effort with Khrushchev. Malenkov "spoke the best Russian of any Soviet leader I have heard", his "speeches were well constructed and logical in their development" and he seemed "a man with a more Western - oriented mind."