After the death of Yakov Sverdlov, he was considered a candidate for the post of Chairman of the All-Russian Central Executive Committee, the head of state of the Russian SFSR, but lost to Mikhail Kalinin.

A member of the Left Opposition associated with Leon Trotsky, he signed the Declaration of 46 in October 1923, making himself a lifelong enemy of future Soviet Leader Joseph Stalin.

He was arrested early in 1908 and as a juvenile, aged 16, was sentenced to confinement in a young offenders' institute, and subsequently exiled to Siberia, where he spent about four years educating himself.

In January 1918, he was appointed as Chairman of the Central Executive Committee of the Ural Regional Soviet amidst the beginning of the outbreak of the Eastern Front of the Russian Civil War.

In June 1918, Beloborodov approved an initiative by the regional Cheka led by Gavril Myasnikov to execute Grand Duke Michael, either in advance, or after the fact.

It was under Beloborodov's administration that the former Emperor Nicholas II, his wife, their five children, and a number of their former retainers were transferred to Yekaterinburg, though it was the military commissar Filipp Goloshchyokin who was in overall charge of the family's incarceration, while Yakov Yurovsky was appointed as commandant of the Ipatiev House, and Pavel Medvedev headed the external guard.

Along with Pyotr Voykov, Beloborodov directed the smuggling of letters written in French to the imprisoned Romanovs at the Ipatiev House, claiming to be a monarchist officer seeking to rescue them, composed at the behest of the Cheka.

These fabricated letters, along with the Romanov responses to them, written either on blank spaces or on the envelope, were ultimately used by the Ural Soviet, and likely the Central Executive Committee in Moscow, to justify murdering the Imperial Family amidst the rapid gains made by the White Army in the region.

Beloborodov and Georgy Safarov would remain at the local Cheka headquarters at the Amerikanskaya Hotel while Goloshchyokin arrived at the Ipatiev House to personally direct the executions.

On 25 March 1919, he was a candidate considered for the post of Chairman of the Central Executive Committee of the All-Russian Congress of Soviets following the death of Yakov Sverdlov, but Mikhail Kalinin was ultimately elected in his place.

He wrote in one of his letters, complaining to Nikolay Krestinsky about the leniency of the sentences being handed down by the local Don Revolutionary Tribunals:[3] This naivety needs to be put to an end, and the sooner the better.

Beloborodov was arrested in 1936, early in Stalin's great purge of the upper echelons of the Communist Party, but resisted making the confession required of him, so although his name was mentioned at the trial of Karl Radek and others in January 1937, he was not produced in court.

In May 1937, Stalin sent a note to Nikolai Yezhov, head of the NKVD, saying: "One might think that prison for Beloborodov is a podium for reading speeches, statements which refer to the activities of all sorts of people but not to himself.