In the next few years, Willoughby became the leader of the Presbyterian force within Parliament, opposed the formation of the New Model Army and was elected as speaker of the House of Lords in July 1647.
However, when the Parliamentary army took London in September, Willoughby was imprisoned along with six other peers and held for four months at which point he was released without charge, fleeing to the Netherlands to join the Royalists.
Now espousing the Royalist cause, Willoughby was promoted to Vice Admiral under the Duke of York, an appointment that may have been designed to engender sympathy among Scots and Presbyterians.
On 25 October 1651, a seven-ship force under Commodore George Ayscue arrived off Barbados, demanding that the island submit "for the use of the Parliament of England".
Willoughby's reply (tellingly addressed to "His Majesty's ship Rainbow") was unyielding, declaring that he knew "no supreme authority over Englishmen but the King".
In early December, with the Royalist cause defeated in England, Ayscue began a series of raids against fortifications on the island and was reinforced by a group of thirteen ships bound for Virginia.
Governor Willoughby attempted to stem the spread of Parliamentary sympathies by hanging two of the returning militia soldiers and prohibiting the reading of documents from the blockading fleet.
While he was twice imprisoned during The Protectorate for involvement in Royalist intrigues, Willoughby survived the Cromwell years and after the Restoration in 1660 he was again appointed to a governorship in the Caribbean, administering the colonies at Saint Kitts, Nevis, Montserrat, and Antigua.
In June 1664 he organised an expedition from Barbados against the small French garrison at Saint Lucia, expelling it under the pretext that a half-Carib native had effectively "sold" it to England and establishing a short-lived English colony there.
During the Second Anglo-Dutch War, Willoughby organised Barbados' defences and managed to repel a Dutch fleet led by Michiel de Ruyter in April 1665.
Finding a force under the English privateer Robert Searle already looting the settlement there, he put a stop to the destruction and installed a garrison of fifty men to maintain order.
In his will, he left extensive holdings in Barbados, Antigua, and Suriname to his children and his nephew Henry Willoughby as well as smaller grants of currency or sugar to various associates and servants.