His political career began with his election to the House of Representatives in 1966. He was returned to Parliament at every general election he contested up to 1998. He was appointed secretary general of the Nationalist party in 1972 and became the party's deputy leader in 1977. He was elected as a representative at the Parliamentary Assembly of the Council of Europe of 1967, remaining a member for almost twenty years. During his career as Minister for the Interior and Justice, De Marco's efforts led to the integration into domestic law of important international conventions, particularly the European Convention on Human Rights. As Minister for the Interior, he pioneered the reforms and modernisations in the Police Force, being instrumental in the founding of the Police Academy.