Krestinsky was born in the town of Mogilev, in what is now Mogilev Region of Belarus. According to Russian archivist A. B. Roginsky, Krestinsky was of ethnic Russian origin. Other sources suggest ethnic Ukrainian origins, while according to Felix Chuev, Vyacheslav Molotov maintained that Krestinsky's family had converted from Judaism to Eastern Orthodoxy.
In late 1920 to early 1921, after the Bolshevik victory in the Russian Civil War, Krestinsky supported Leon Trotsky's faction in an increasingly bitter dispute over the direction of the country. After Vladimir Lenin's victory at the tenth party congress in March 1921, Krestinsky lost his Politburo, Orgburo and Secretariat posts and became Soviet ambassador to Germany. The post was an important and sensitive one because of Soviet Russia's crucial and delicate relationship with Germany at the time, but not nearly as important as his previous posts. Krestinsky supported Trotsky and the Left Opposition in 1923–early 1927, but distanced himself from Trotsky later in 1927. He completely broke with the opposition in April 1928.
Show trial
Krestinsky continued working as a diplomat until 1937, when he was arrested during the Great Purge. He was put on trial on 12 March 1938. While almost all other defendants admitted their guilt during the Moscow Show Trials, Krestinsky at first denied everything, but reversed himself the following day. On 2 March he said to the presiding judge, Vasili Ulrikh:
I do not recognize that I am guilty. I am not a Trotskyite. I was never a member of the "right-winger and Trotskyite bloc", which I did not know to exist. Nor have I committed a single one of the crimes imputed to me, personally; and in particular I am not guilty of having maintained relations with the German Secret Service.
The following day, he made a total reversal of his position:
Yesterday, under the influence of a momentary keen feeling of false shame, evoked by the atmosphere of the dock and the painful impression created by the public reading of the indictment, which was aggravated by my poor health, I could not bring myself to tell the truth, I could not bring myself to say that I was guilty. And instead of saying, "Yes, I am guilty," I almost mechanically answered, "No, I am not guilty."
Such a reversion was a rare episode in the show trials of the late 1930s. Krestinsky was sentenced to death and executed in March 1938. He was partially exonerated during Nikita Khrushchev's De-Stalinization program. Krestinsky was cleared of all charges during Mikhail Gorbachev's perestroika reforms.