The Tsardom of Russia continued its territorial growth through the 17th century. In the southwest, it claimed eastern Ukraine's lands, which had been under Polish–Lithuanian rule and sought assistance from the Tsardom to leave the rule of the Commonwealth. The Zaporozhian Cossacks, warriors organized in military formations, lived in the frontier areas bordering Poland, the Crimean Tatar lands. Although part of them was serving in the Polish army as Registered Cossacks, the Zaporozhian Cossacks remained fiercely independent and staged a number of rebellions against the Poles. In 1648, the peasants of what is now Ukraine joined the Cossacks in rebellion during the Khmelnytsky Uprising, because of the social and religious oppression they suffered under Polish rule. Initially, Cossacks were allied with Crimean Tatars, which had helped them to throw off Polish rule. Once the Poles convinced the Tartars to switch sides, the Zaporozhian Cossacks needed military help to maintain their position.

In 1648 the Hetman (leader) of the Zaporozhian Host, Bohdan Khmelnytsky, offered to ally with the Russian tsar, Aleksey I. Aleksey's acceptance of this offer, which was ratified in the Treaty of Pereyaslav in 1654, led to a protracted war between Poland and Russia. The Truce of Andrusovo, which did not involve the Hetmanate (Cossack Hetmanate) as a participating party of the agreement ended the war in 1667. As a result, it split Ukrainian territory along the Dnieper River, reuniting the western sector (or Right-bank Ukraine) with Poland and leaving the eastern sector (Left-bank Ukraine) self-governing under the sovereignty of the tsar. However, the self-government did not last long and Eastern Ukrainian territory was eventually incorporated into the Russian Empire (after the Battle of Poltava) during the 18th century.