An exponent of doctrinaire economic liberalism and a strong advocate of free trade, Frère-Orban played a prominent part in the Liberal movement while practicing law in Liège. He was sent in 1847 to the Chamber of Representatives as a member from that city. From 1847 to 1894 he served as the leading Liberal member of the lower house in addition to holding many ministerial posts. As minister of finance (1848–52), he founded the Banque Nationale, abolished the newspaper tax, reduced the postage, and modified the customs duties as a preliminary to a free-trade policy.

To facilitate negotiations for a new commercial treaty, he conceded to France a law of copyright, which proved highly unpopular in Belgium. He resigned and the rest of the Cabinet soon followed him. While serving again as finance minister in 1857, he embodied his free-trade principles in commercial treaties with Great Britain and France and abolished the octroi duties (local import taxes) and tolls on national roads. After becoming prime minister in 1868, he defeated a French attempt to gain control of the Luxembourg railways (1869). In his second term as prime minister, he provoked the bitter opposition of Belgium's Catholic party by establishing secular primary education (1879) and by breaking off diplomatic relations with the Vatican (1880). Although Frère-Orban grudgingly conceded an extension of the franchise (1883), the hostility of the Radicals and the discontent caused by a financial crisis resulted in the overthrow of his government in the elections of 1884. He continued to lead the Liberal opposition until 1894.