The only son of Sir Thomas Windebank of Hougham, Lincolnshire, who owed his advancement to the Cecil family, Francis entered St John's College, Oxford, in 1599, coming there under the influence of William Laud. After a few years' continental travel (1605-1608), he was employed for many years in minor public offices, and became clerk of the council. In June 1632 he was appointed by King Charles I as secretary of state in succession to Lord Dorchester, his senior colleague being Sir John Coke, and he was knighted. His appointment was mainly due to his Spanish and Roman Catholic sympathies. The first Earl of Portland, Francis, Lord Cottington, and Windebank formed an inner group in the council, and with their aid the king carried on various secret negotiations, especially with Spain.
In December 1634 Windebank was appointed to discuss with the papal agent Gregorio Panzani the possibility of a union between the Anglican and Roman Churches, and expressed the opinion that the Puritan opposition might be crippled by sending their leaders to the war in the Netherlands. Windebank's efforts as treasury commissioner in 1635 to shield some of those guilty of corruption led to a breach with Archbishop Laud, and the next year he was for a time disgraced for issuing an order for the conveyance of Spanish money to pay the Spanish troops in the Netherlands.
In July 1638 he urged the king to make war with the Scots, and in 1640, when trouble was breaking out in England, he sent an appeal from Queen Henrietta Maria to the pope for money and men. He was elected in March 1640 to the Short Parliament, as member for Oxford University, and he entered the Long Parliament in October as member for Cone. In December the House learnt that he had signed letters of grace to recusant priests and Jesuits, and summoned him to answer the charge, but the king allowed him to escape to France. From Calais he wrote to Christopher Hatton, defending his integrity, and affirming his belief that the Church of England was the purest and nearest the primitive Church. He remained in Paris until his death, shortly after he had been received into the Roman communion.