Maria Spiridonova descended from the nobility, she was born in the Tambov governorate. Spiridonova studied at the Tambov female gymnasium, but was expelled from the 8 year for misbehaviour (1902). She worked as a clerk in the governorate nobility assembly. Since 1905, she joined the Socialist Revolutionary Party (SRs). In January 1906, Spiridonova carried out the decision of the Tambov organization of the SRs. In the town of Borisoglebsk, she mortally wounded Gavriil Luzhenovsky, the adviser of the Tambov governorate government, who had participated in the suppression of peasant uprisings. She was sentenced to death. The news that she was beaten brutally by the police sparked a wave of protests. Under their influence, the death penalty was commuted to indefinite hard labor. In 1906–1917, she served a sentence in Nerchinsk katorga [hard labour].

Spiridonova was released in March 1917 by order of the Minister of Justice of the Provisional Government, Aleksander Kerensky. May 1917 saw her arrive in Moscow. She became the leader of the left wing of Socialist Revolutionaries, worked in the Petrograd organization of the Party. She supported the October coup. In November 1917, she was the leader of the Left Socialist Revolutionary Party (Internationalists). She had been a member of the Central Committee of the Party until July 1918.

She advocated the formation of a government consisting of the Bolsheviks and Left Socialist Revolutionaries (it acted in December 1917 – March 1918). Chairperson of the Extraordinary (November) and 2nd (November to December) All-Russian Congresses of Soviets of Peasant Deputies. She was a candidate for Chairperson of the Constituent Assembly from the Left SRs and Bolsheviks but lost the vote to Viktor Chernov.

In January–July 1918, she was a member and Chairperson of the Peasant Section of the All-Russian Central Executive Committee (VTsIK).

In March 1918, Spiridonova approved the conclusion of the Treaty of Brest-Litovsk. In June, she spoke out against the consequences of the Treaty, as well as the Bolsheviks' extraordinary food policy, Prodrazvyorstka [a policy and campaign of confiscation of grain and other agricultural products from peasants at nominal fixed prices according to specified quotas food appropriation]. She was an initiator of the assassination of the German envoy Wilhelm von Mirbach by the Left SRs in order to provoke a war with Germany (on July 6, 1918). The Bolsheviks took advantage of the situation to accuse the Left SRs of rebellion against Soviet power. Spiridonova was arrested on the same day at a meeting of the 5th All-Russian Congress of Soviets in Moscow. November 1918 saw her sentenced to one year in prison for her involvement in the Left SR uprising but was amnestied the next day for her merits to the revolution and released.

At the beginning of 1919, she was arrested again, on charges of anti-Soviet activity, sentenced to one year’s incarceration in the Kremlin hospital, which effectively meant her isolation from political and public life. In April 1919, she fled, went underground, carried out the party work, headed the Left SR Central Committee minority opposing the agreement with Bolsheviks. In October 1920, she was rearrested, placed in the All-Russian Extraordinary Commission (VChK) medical facility, then confined in a psychiatric prison. In November 1921, she was released under the condition that she cease and desist all political activity.

In 1923–1937, Spiridonova was in administrative exile and was repeatedly arrested. In January 1938, she was eventually sentenced to 25 years in prison by the Military Collegium of the Supreme Court of the USSR on charges of counterrevolutionary terrorist activities. On September 11, 1941, Spiridonova was executed in the Medvedevsky Forest massacre near Oryol. She was fully rehabilitated in 1992.