In 1916, Molotov became a member of the Bolshevik Party's committee in Petrograd. When the February Revolution occurred in 1917, he was one of the few Bolsheviks of any standing in the capital. Under his direction Pravda took a turn "left" in opposing the Provisional Government which was formed after the revolution. Consequently, when Stalin returned to the capital, he reversed Molotov's line. However, when the party leader, Vladimir Lenin, arrived, he overruled Stalin. Despite this, Molotov became a protégé and close adherent of Stalin, an alliance to which he owed not only his later prominence, but almost certainly his life as well; Molotov was one of only five of the leading Old Bolsheviks to survive the Great Purges. The other four were Kalinin (d. 1946), Alexandra Kollontai (d. 1952), Stalin himself (d.1953) and Kliment Voroshilov (d.1969). Molotov became a member of the Military Revolutionary Committee which planned the October Revolution (effectively bringing the Bolsheviks to power).

In 1918, Molotov was sent to Ukraine to take part in the civil war then breaking out. Since he was not a military man, Molotov took no part in the fighting. In 1920, he became secretary to the Central Committee of the Ukrainian Bolshevik Party. Lenin recalled him to Moscow in 1921, elevating him to full membership in the Central Committee and Orgburo, and putting him in charge of the party secretariat. In 1922, Stalin became General Secretary of the Bolshevik Party with Molotov as the de facto "second" secretary. Under Stalin's patronage, Molotov became a member of the Politburo in 1926.

During the power struggles which followed Lenin's death in 1924, Molotov remained a loyal supporter of Stalin against his various rivals: first Leon Trotsky, later Lev Kamenev and Grigory Zinoviev and finally Nikolai Bukharin. He became a leading figure in the "Stalinist centre" of the party, which also included Kliment Voroshilov, Lazar Kaganovich, Sergo Ordzhonikidze and Sergei Kirov. Trotsky and his supporters underestimated Molotov as many others did. Trotsky called him "mediocrity personified", whilst Molotov himself pedantically corrected comrades referring to him as 'Stone-Arse' by saying that Lenin had actually dubbed him 'Iron Arse'. However, this outward dullness concealed a sharp mind and great administrative talent. He operated mainly behind the scenes and cultivated an image as a colourless bureaucrat - for example, he was the only Bolshevik leader who always wore a suit and tie (Lenin's attire routine changed in the later years).

When Bukharin's ally, Alexei Rykov, was removed as Chairman of the Council of People's Commissars (the equivalent of a prime minister) in December 1930, Molotov succeeded him. In this post, he oversaw the Stalin regime's collectivisation of agriculture. Molotov carried out Stalin's line of using a combination of force and propaganda to crush peasant resistance to collectivisation, including the deportation of millions of kulaks (peasants with property) to labour camps. An enormous number of the deportees died from exposure and overwork. He signed the "Law of Spikelets" and personally led the Extraordinary Commission for Grain Delivery in Ukraine, which seized a reported 4.2 million tonnes of grain from the peasants, during a widespread manmade famine (known in Ukraine as Holodomor). Contemporary historians estimate that between seven and eleven million people died, either of starvation or in labour camps, in the move to collectivise farms. Molotov also oversaw the implementation of the first Five-Year Plan for rapid industrialisation.

Sergei Kirov was assassinated in 1934, which is now believed by some historians (notably Edvard Radzinsky in his book Stalin) to have been ordered by Stalin, triggering a second crisis, the Great Purge. This purge acquired momentum through 1935 and 1936 and culminated in 1937-38 in the Moscow Trials, in which most of the pre-Stalin Bolshevik leaders were convicted on usually fabricated charges of treason and espionage, and millions of other Russians were deported to labour camps. Although the purges were carried out by Stalin's successive police chiefs, Genrikh Yagoda, Nikolai Yezhov and Lavrenty Beria, Molotov was intimately involved in the processes. Stalin frequently required him and other Politburo members to sign the death warrants of prominent purge victims, and Molotov always did so without question. There is no record of Molotov attempting to moderate the course of the purges or even to save individuals, as some other Soviet leaders did. During the Great Terror, he personally approved 372 documented execution lists, more than any other Soviet official, including Stalin himself.

Despite the great human cost, the Soviet Union under Molotov's nominal prime ministership made great strides in the adoption and widespread implementation of agrarian and industrial technology. The rise of Adolf Hitler in Nazi Germany gave the development of a modern armaments industry great urgency and Molotov and the commissar of industry, Lazar Kaganovich, were primarily responsible for guiding this success. Ultimately, it was this arms industry, along with American Lend-Lease aid, which enabled the Soviet Union to prevail in World War II. However, the purges of the Red Army leadership, in which Molotov participated, weakened the Soviet Union's defence capacity. This somewhat contributed to the military disasters of 1941 and 1942, which were mostly caused by unreadiness for war. It also led to the dismantling of the peasant class and its replacement by collectivised agriculture left a legacy of chronic agricultural under-production which the Soviet regime never fully overcame.

Following the purges, Molotov was generally regarded as Stalin's deputy and as his long-term successor, although Molotov was careful not to encourage any such suggestion. The American journalist John Gunther wrote in 1938: "Molotov has a fine forehead, and looks and acts like a French professor of medicine - orderly, precise, pedantic. He is... a man of first-rate intelligence and influence. Molotov is a vegetarian and a teetotaller. Stalin gives him much of the dirty work to do".

In 1939, following the Munich Agreement and Hitler's subsequent invasion of Czechoslovakia in 1938, Stalin believed that Britain and France would not be reliable allies against German expansion so instead sought to conciliate Germany. In May 1939, Foreign Minister Maxim Litvinov (who, in addition to being Jewish, was also viewed as pro-Western) was dismissed, and Molotov was appointed to succeed him. Molotov remained at the head of the Sovnarkom until May 1941, when Stalin took over as the official head of the Soviet government.

At first, Hitler rebuffed Soviet diplomatic hints that Stalin desired a treaty, but in early August, he authorised Foreign Minister Joachim von Ribbentrop to begin serious negotiations. A trade agreement was concluded on 18 August, and on 22 August, Ribbentrop flew to Moscow to conclude a formal non-aggression treaty. Although the treaty is known as the Molotov-Ribbentrop Pact, Molotov and Ribbentrop acted only as agents for their masters, Stalin and Hitler. The most important part of the agreement was the secret protocol, which provided for the partition of Poland, Finland and the Baltic States between Nazi Germany and the Soviet Union and for the Soviet annexation of Bessarabia (then part of Romania, now Moldova). This protocol gave Hitler the green light for his invasion of Poland, which began on 1 September.Under the terms of the Pact, Stalin was, in effect, given authorisation to occupy and annex Estonia, Latvia and Bessarabia, as well as the part of Poland east of the Curzon Line (an area in which Ukrainians and Belorussians comprised the majority of the population). He was also given a free hand in relation to Finland. In the Soviet-Finnish War that ensued, a combination of fierce Finnish resistance and Soviet mismanagement resulted in Finland losing parts of its territory, but not its independence. During this conflict, the Finns coined the term Molotov cocktail for a homemade incendiary device to be used against tanks. Germany was authorised to occupy the western two-thirds of Poland (much of which was annexed to Germany), as well as Lithuania, but the Pact was later amended to allocate Lithuania to the Soviet sphere in exchange for a more favourable border in Poland. All these annexations led to massive suffering and loss of life in the countries which were occupied and partitioned by the two dictatorships. In November 1940 Stalin sent Molotov to Berlin to meet von Ribbentrop and Hitler.

The Molotov-Ribbentrop Pact governed Soviet-German relations until June 1941 when Hitler, having occupied France and neutralised Britain, turned east and attacked the Soviet Union. Molotov was also responsible for telling the Soviet people of the attack, when he announced the war, instead of Joseph Stalin. His speech, broadcast by radio on June 22, played in Russia a role similar to Winston Churchill's wartime speeches in Britain.

Following the invasion, Molotov conducted urgent negotiations with Britain and, later, the United States for wartime alliances. Via Pe-8 bomber he travelled over the frontline to London and Washington in May 1942. The flight over territories occupied by Germany, scanned by AAA's and Luftwaffe, was so difficult and dangerous, that Molotov's pilot, Endel Puusepp, was made Hero of the Soviet Union for completing it. Upon arrival Molotov signed the Anglo-Soviet Treaty of Alliance and also secured Franklin D. Roosevelt and Winston Churchill's agreement to create a "second front" in Europe.

Molotov accompanied Stalin to the Teheran Conference in 1943, the Yalta Conference in 1945 and the Potsdam Conference, which followed the defeat of Germany. He represented the Soviet Union at the San Francisco Conference, which created the United Nations. Even during the period of wartime alliance, Molotov was known as a tough negotiator and determined defender of Soviet interests. In this he was carrying out Stalin's wishes. From 1945 to 1947 Molotov took part in all four conferences of foreign ministers of the victorious states in the Second World War. In general, he was distinguished by an uncooperative attitude towards the Western powers. Winston Churchill in his wartime memoirs lists many meetings with Molotov. Acknowledging him as a "man of outstanding ability and cold-blooded ruthlessness", Churchill concluded: "In the conduct of foreign affairs, Mazarin, Talleyrand, Metternich, would welcome him to their company, if there be another world to which Bolsheviks allow themselves to go."

In the postwar period, Molotov's position began to decline. In 1949, he was replaced as Foreign Minister by Andrey Vyshinsky, although retaining his position as Deputy Prime Minister and membership on the Politburo. Following the death of Andrei Zhdanov, who had come to be seen as Stalin's most likely successor, Stalin and Beria began to plan a new purge, which would have removed most of the older party leaders, such as Molotov, from their positions. New leaders, such as Georgii Malenkov and Nikita Khrushchev, enjoyed Stalin's patronage. A clear sign of Molotov's precarious position was his inability to prevent the arrest of his Jewish wife, Polina Zhemchuzhina, whom Stalin had long distrusted, in December 1948 for "treason". The couple were reunited by Beria upon the death of Stalin. At the 19th Party Congress in 1952, Molotov was elected to the new, expanded Presidium of the Communist Party but was excluded from the smaller standing committee of the Presidium (although this was not made public). It seems likely that Stalin's death in March 1953 saved Molotov from being purged as part of a "clean out" of the Soviet leadership.

Following Stalin's death, a realignment of the leadership was sought, in the course of which Molotov's position was strengthened. Beria was purged and executed, and Molotov regained the Foreign Ministry under Malenkov as Prime Minister. However, the new Party Secretary, Khrushchev, soon emerged as the real power in the regime. He presided over a gradual domestic liberalisation and a thaw in foreign policy, shown by the reconciliation with Tito's government in Yugoslavia (which Stalin had expelled from the communist movement). Molotov, an old-guard Stalinist, seemed increasingly out of place in this new environment, but he represented the Soviet Union at the Geneva Conference of 1955.

The events which led to Molotov's downfall began in February 1956 when Khrushchev launched an unexpected denunciation of Stalin at the 20th Congress of the Communist Party. Khrushchev attacked Stalin, both over the purges of the 1930s and the defeats of the early years of World War II, which he blamed on Stalin's over-trusting attitude to Hitler and the purges of the Red Army. Since Molotov was most senior of Stalin's collaborators still alive and had played a leading role in the purges, it became obvious that Khrushchev's examination into the past would probably result in Molotov's fall from power. Consequently, he became the leader of the old guard in resisting Khrushchev, although whether he actually plotted to overthrow Khrushchev, as was later alleged, is not clear. In June 1956, Molotov was removed as Foreign Minister, and in June 1957 was expelled from the Presidium (Politburo) following a failed attempt to remove Khrushchev as First Secretary. Although Molotov's faction initially won a vote in the Presidium, 7-4, to remove Khrushchev, the latter refused to resign unless a Central Committee plenum decided so. In the plenum, which lasted from 22–29 June, Molotov and his faction were defeated. Eventually he was banished as ambassador to Mongolia. In 1960, he was appointed Soviet representative to the International Atomic Energy Agency, which was seen as a partial rehabilitation. However, after the 22nd Party Congress in 1961, during which Khrushchev carried his de-Stalinisation campaign to remove Stalin's body from Lenin's Mausoleum, Molotov was removed from all positions and expelled from the Communist Party. In March 1962, it was announced that Molotov had retired from public life.

In retirement, Molotov remained totally unrepentant regarding his role during Stalin's rule. After the Sino-Soviet split, it was reported that he agreed with the criticisms made by Mao Zedong of the supposed "revisionism" of Khrushchev's policies. According to Roy Medvedev, Stalin's daughter Svetlana recalled Molotov and his wife telling her: "Your father was a genius. There's no revolutionary spirit around nowadays, just opportunism everywhere. China's our only hope! Only they have kept alive the revolutionary spirit". In 1976, he said:

"The fact that atomic war may break out, isn't that class struggle? There is no alternative to class struggle. This is a very serious question. The be-all and end-all is not peaceful coexistence. After all, we have been holding on for some time, and under Stalin we held on to the point where the imperialists felt able to demand point-blank: either surrender such and such positions, or it means war. So far the imperialists haven't renounced that."

Vyacheslav Molotov died on November 8, 1986, one day past the 69th anniversary of the Bolshevik revolution and five years before the dissolution of the Soviet Union. He was 96 years old at the time of his death.

Molotov was partly rehabilitated during the Brezhnev years and was allowed to rejoin the Communist Party in 1984 under Konstantin Chernenko. At the time of his death, he was the last surviving major participant in the events of 1917. He was buried at the Novodevichy Cemetery, Moscow. A collection of interviews with Molotov, Molotov Remembers: Inside Kremlin Politics, was published posthumously by Felix Chuev. In 2005 Molotov's grandson and namesake, Russian political scientist Vyacheslav Nikonov (born in 1956), wrote an early biography of him.

At the end of 1989, two years before the final collapse of the Soviet Union, the Congress of People's Deputies of the Soviet Union and Mikhail Gorbachev's government formally denounced the Molotov-Ribbentrop Pact, acknowledging that the annexation of the Baltic States and the partition of Poland had been illegal.