The marriage was a complete failure; the following 18 years were filled with deception and humiliation for her.

Catherine, however, would not have become empress if her husband had been at all normal. He was extremely neurotic, rebellious, obstinate, perhaps impotent, nearly alcoholic, and, most seriously, a fanatical worshipper of Frederick II of Prussia, the foe of the empress Elisabeth. Catherine, by contrast, was clearheaded and ambitious. Industrious, highly intelligent and strong-willed, she quickly mastered the Russian language. Her flexibility of character, and love of Russia gained her much support. A reader of historical and philosophical works, she entered into correspondence with some of the greatest minds in Europe, including Voltaire.

On June 28, 1762, with the support of the Imperial Guard, she overthrew her husband Peter III and had herself proclaimed empress and autocrat in the Cathedral of our Lady of Kazan. Peter III abdicated and was assassinated eight days later. Although Catherine probably did not order the murder of Peter, it was committed by her supporters, and public opinion held her responsible.

She was crowned Empress of All Russia on September 22, 1762, in the Dormition Cathedral of the Moscow Kremlin. Her rule (34 years) was one of the most prosperous periods of the Russian Empire. She undertook a wide range of internal political reforms, waged two successful wars against the Ottoman Empire and occupied vast territories on Russia's southern boundaries, eventually advancing the country's border to the Black Sea.

She died on November 6, 1796, and was buried in the Cathedral of the St. Peter and St. Paul Fortress in St. Petersburg.