The dynasty's progenitor, Niklot (1090–1160), was a chief of the Slavic Obotrite tribal federation, who fought against the advancing Saxons and was finally defeated in 1160 by Henry the Lion in the course of the Wendish Crusade. Niklot's son, Pribislav, submitted himself to Henry, and in 1167 came into his paternal inheritance as the first Prince of Mecklenburg.
After several divisions among Pribislav's descendants, Henry II of Mecklenburg (1266–1329) until 1312 acquired the lordships of Stargard and Rostock, and bequeathed the reunified Mecklenburg lands – except the County of Schwerin and Werle – to his sons, Albert II and John. After they both had received the ducal title, the former lordship of Stargard was recreated as the Duchy of Mecklenburg-Stargard for John in 1352. Albert II retained the larger western part of Mecklenburg, and after he acquired the former County of Schwerin in 1358, he made Schwerin his residence.
In 1363 Albert's son, Duke Albert III, campaigned in Sweden, where he was crowned king one year later. In 1436, William, the last Lord of Werle, died without a male heir. Because William's son-in-law, Ulric II of Mecklenburg-Stargard, had no issue, his line became extinct upon Ulric's death in 1471. All possessions fell back to Duke Henry IV of Mecklenburg-Schwerin, who was then the sole ruler over all of Mecklenburg.
Mecklenburg-Schwerin began its existence during a series of constitutional struggles between the duke and the nobles. The heavy debt incurred by Karl Leopold, who had joined Russian Empire in a war against Kingdom of Sweden, brought matters to a crisis; Charles VI interfered, and in 1728 the imperial court of justice declared the duke incapable of governing. His brother, Christian Ludwig II, was appointed administrator of the duchy. Under this prince, who became ruler de jure in 1747, the Convention of Rostock, by which a new constitution was framed for the duchy, was signed in April 1755. By this instrument, all power was in the hands of the duke, the nobles, and the upper classes generally; the lower classes were entirely unrepresented. During the Seven Years' War, Frederick II took up a hostile attitude towards Frederick the Great, and in consequence Mecklenburg-Schwerin was occupied by the Kingdom of Prussia. In other ways his rule was beneficial to the country. In the early years of the French Revolutionary Wars, Frederick Francis I remained neutral, and in 1803 he regained Wismar from Kingdom of Sweden. In 1806 the land was overrun by the First French Empire, and in 1808 he joined the Confederation of the Rhine. He was the first member of the confederation to abandon Napoleon, to whose armies he had sent a contingent, and in 1813–1814 he fought against France.