Ruled by the successors of the Nikloting House of Mecklenburg, Mecklenburg-Schwerin remained a state of the Holy Roman Empire along the Baltic Sea littoral between Holstein-Glückstadt and the Duchy of Pomerania.

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.

Both were deposed in 1628 by Albrecht von Wallenstein, as they had supported Christian IV of Denmark in the Thirty Years' War.

The emperor and the rulers of Sweden and of the Electorate of Brandenburg took part in this struggle, which was intensified three years later, when on the death of Gustav Adolph, the family ruling over Mecklenburg-Güstrow became extinct.

In 1701, with the endorsement of the Imperial state of the Lower Saxon Circle, the Treaty of Hamburg (1701) was signed and the final division of the country was made.

Continued conflicts and partitions weakened the rule of the dukes and affirmed the reputation of Mecklenburg as one of the most backward territories of the Empire.

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.

In the early years of the French Revolutionary Wars, Frederick Francis I, Grand Duke of Mecklenburg-Schwerin remained neutral, and in 1803 he regained Wismar from the Kingdom of Sweden.

On 1 January 1934 it was united with the neighbouring Free State of Mecklenburg-Strelitz (both today part of the Germany's Bundesland Mecklenburg-Vorpommern).