In 1921 a Sobor created the Ukrainian Autocephalous Orthodox Church (UAOC) in Kiev and ordained Metropolitan Wasyl Lupkivskyj as head of the UAOC. THE UAOC was at that point independent of all other churches. It obtained its autocephaloous status a few years later in 1924 when Gregory VII, Patriarch of Constantinople, Ecumenical Patriarch, issued a tomos re-establishing the Kyivan-Rus (Ukrainian) Metropolitanate as an Autocephalous Church. The responsibility of establishing a new Synod of Bishops was given to the Metropolitan-Archbishop of Warsaw, Dionisij Waledynskyj. Autocephaly refers to the self-governing status of a particular national church that is recognized by other Orthodox jurisdictions. In wake of the break up of the Russian Empire some national groups sought autonomy (Autonomous Orthodox church bodies are not the same as Autocephalic church bodies) from Moscow. The Soviet government persecuted the UAOC; and the Russian Orthodox Church (ROC) also prevented the UAOC from establishing their ecclesiastical order for some time. Between the wars the UAOC was tolerated by the ROC and it was allowed to exist on Ukranian Soviet territory.

On October 8, 1942 Archbishop Nikanor and Bishop Mstyslav (now Patriarch) of the UAOC and Metropolitan Oleksiy (Hromadsky) of the Ukrainian Autonomous Orthodox Church entered into an Act of Union at the Pochaev Lavra uniting these two church hierarchies. German occupation authorities and pro-Russian hierarchs of the Autonomous Church forced Metropolitan Oleksiy to remove his signature. Metropolitan Oleksiy was executed in Volynia on May 7, 1943.

The Russian Orthodox Church regained its general monopoly after World War II in the Ukranian SSR. Most of the other churches were forced out as the Soviet government only recognized the Moscow Patriarchate, revived at the time of the Russian Revolution, as the only legitimate church in most of the Soviet Union. Many accused it of being a puppet of the Communist Party. After the suspicious death of Tikhon of Moscow these autocephalic churches sought to remain independent; something that Moscow tolerated until after World War Two when many Ukranian Orthodox clergy not affiliated with Moscow fled to Germany or the United States. The UAOC in Ukraine was then liquidated by the Soviets with the assistance of the Patriarchate of Moscow. Any UAOC hierarchs or clergy who remained in Ukraine and refused to join the Russian Church were executed or sent to concentration camps. A few years later the same thing happened to the Ukrainian Greek Catholic Church in Western Ukraine and Transcarpathia.