At the age of 15, when he was brought to Vienna, he was established in the Silesian Duchy of Teschen, which had been mediatised and granted to his father by the Emperor in 1722. Francis succeeded his father as Duke of Lorraine in 1729. In 1731 he was initiated into freemasonry (Grand Lodge of England) by John Theophilus Desaguliers at a specially convened lodge in The Hague at the house of the British Ambassador, Philip Stanhope, 4th Earl of Chesterfield. During a subsequent visit to England, Francis was made a Master Mason at another specially convened lodge at Houghton Hall, the Norfolk estate of British Prime Minister Robert Walpole.
Maria Theresa arranged for Francis to become "Lord Lieutenant" (locumtenens) of Hungary in 1732. He was not excited about this position, but Maria Theresa wanted him closer to her. In June 1732 he agreed to go to Pressburg.
A preliminary peace was concluded in October 1735 and ratified in the Treaty of Vienna in November 1738. Under its terms, Stanisław I, the father-in-law of King Louis XV and the losing claimant to the Polish throne, received Lorraine, while Francis, in compensation for his loss, was made heir to the Grand Duchy of Tuscany, which he would inherit in 1737.
They married on 12 February in the Augustinian Church, Vienna. The wedding was held on 14 February 1736. The (secret) treaty between the Emperor and Francis was signed on 4 May 1736. In January 1737, the Spanish troops withdrew from Tuscany, and were replaced by 6,000 Austrians. On 24 January 1737 Francis received Tuscany from his father-in-law. Until then, Maria Theresa was Duchess of Lorraine.
Gian Gastone de' Medici, who died on 9 July 1737, was the second cousin of Francis (Gian Gastone and Francis' father Leopold were both great-grandchildren of Francis II, Duke of Lorraine), who also had Medici blood through his maternal great-great-grandmother Marie de' Medici, Queen consort of France and Navarre. In June 1737 Francis went to Hungary again to fight against the Turks. In October 1738 he was back in Vienna. On 17 December 1738 the couple travelled south, accompanied by his brother Charles to visit Florence for three months. They arrived on 20 January 1739.
Maria Theresa secured in the Treaty of Füssen his election to the Empire on 13 September 1745, in succession to Charles VII, and she made him co-regent of her hereditary dominions.
Maria Theresa and Francis I had sixteen children, amongst them the last pre-revolutionary queen consort of France, their youngest daughter, Marie Antoinette (1755–1793). Francis was succeeded as Emperor by his eldest son, Joseph II, and as Grand Duke of Tuscany by his younger son, Peter Leopold (later Emperor Leopold II). Maria Theresa retained the government of her dominions until her own death in 1780.
He died suddenly in his carriage while returning from the opera at Innsbruck on 18 August 1765. He is buried in tomb number 55 in the Imperial Crypt in Vienna.
Francis was well content to leave the wielding of power to his able wife. He had a natural fund of good sense and brilliant Business capacity and was a useful assistant to Maria Theresa in the laborious task of governing the complicated Austrian dominions, but he was not active in politics or diplomacy. However, his wife left him in charge of the financial affairs, which he managed well until his death. Heavily indebted and on the verge of bankruptcy at the end of the Seven Years' War, the Austrian Empire was in a better financial condition than France or England in the 1780s. He also took a great interest in the natural sciences. He was a member of the Freemasons.