Born in Cölln on the Spree, George William was the son of John Sigismund, Margrave of Brandenburg and Anna of Prussia. His maternal grandfather was Albert Frederick, Duke of Prussia.  In 1616 George William married Elisabeth Charlotte of the Palatinate. Their only son Frederick William later became known as the “Great Elector”. Of his two daughters, the eldest, Louise Charlotte, married Jacob Kettler, Duke of Courland, and the younger, Hedwig Sophie, married William VI, Landgrave of Hesse-Kassel.  In 1619 George William inherited the Margravate of Brandenburg and the Duchy of Prussia. He paid his feudal homage in person to the King of Poland, Zygmunt Waza, in September 1621 in Warsaw (the Duchy of Prussia was a fief of the Kingdom of Poland at the time). The homage was renewed in 1633 after the election of a new Polish king, Władysław IV Waza.  During the Thirty Years’ War, George William tried to remain neutral between the Roman Catholic forces of the Holy Roman Empire and the Protestant principalities. As his sister Maria Eleonora of Brandenburg was queen of Sweden, George William had to maneuver between requests of assistance from his Protestant brother-in-law King Gustavus Adolphus of Sweden and his own Protestant counsellors on one side and his Catholic chancellor Count Adam von Schwarzenberg on the other.

Despite his attempts at neutrality, George William was forced by Gustavus Adolphus to join the Protestant forces in 1631. His rule was largely weak and ineffective, as much of government responsibilities in Brandenburg-Prussia was turned over to Schwarzenberg as the country suffered greatly during the war. Protestant and Catholic troops alike burned and plundered the region and the population was decimated there as it was throughout the German states.  With his brother-in-law Gustavus dead in 1632, George William maintained the Swedish alliance until after the Swedish defeat at the Battle of Nordlingen on 6 September 1634. At that point, George William withdrew Brandenburg from the war and signed the Peace of Prague with Emperor Ferdinand II on 30 May 1635. Leaving Schwarzenberg in charge of the government, George William withdrew in 1637 to the relatively safe region of the Duchy of Prussia, where he lived in retirement until his death at Königsberg in 1640.