Called to the bar in 1612, Selden practiced as a conveyancer, rarely appearing in court. His first major book, Titles of Honour (1614), has remained a useful reference. Analecton Anglo-Britannicon (1615) was a history of civil government in Britain before the Norman Conquest (1066). His reputation as an Orientalist was based on De diis Syris Syntagmata (1617), which was chiefly concerned with Middle Eastern polytheism, and on later works dealing with the calendar, marriage law, and judicial administration of the ancient Jews. With Patrick Young and Richard James he compiled (1628) a catalog of the sculpture collection known as the Arundel marbles. In 1647 he published the first printed edition of the old English lawbook Fleta.

Selden's History of Tythes (1618), although conceding the legal right of the Church of England to collect tithes, denied divine authority for the practice. The book was suppressed, and the Privy Council forced the author to recant. Twice he was imprisoned for taking the side of the House of Commons (to which he was elected in 1623) against King Charles I. Later becoming a Royalist, however, Selden dedicated to the king Mare clausum (1635), a justification of a single nation's rule over the high seas, in rebuttal to Hugo Grotius' Mare liberum (1609). From 1640, having reversed his political position once more, he took part in the Commons' proceedings against William Laud, archbishop of Canterbury, and against Charles I himself.