The Commissioners for the Fifty New Churches Act of 1711 realised that, due to rapid development in the Bloomsbury area during the latter part of the 17th and early part of the 18th centuries, the area (then part of the parish of St Giles in the Fields) needed to be split off and given a parish church of its own. They appointed Nicholas Hawksmoor, a pupil and former assistant of Sir Christopher Wren, to design and build this church, which he then did between 1716 and 1731. This was the sixth and last, of his London churches. St George's was consecrated on 28 January 1730 by Edmund Gibson, Bishop of London. The stepped tower is influenced by Pliny the Elder's description of the Mausoleum at Halicarnassus, and topped with a statue of King George I in Roman dress. Its statues of fighting lions and unicorns symbolise the recent end of the First Jacobite Rising. The Portico is based on that of the Temple of Bacchus in Baalbek, Lebanon.

The tower is depicted in William Hogarth's well-known engraving "Gin Lane" (1751). Charles Dickens used St George's as the setting for "The Bloomsbury Christening" in Sketches by Boz.

The statue of George I was humorously described by Horace Walpole in a rhyme: “ When Henry VIII left the Pope in the lurch, The Protestants made him the head of the church, But George's good subjects, the Bloomsbury people Instead of the church, made him head of the steeple. ”