Domeyko enrolled at Vilnius University, then known as the Imperial University of Vilna, in 1816 as a student of mathematics and physics. He studied under Jędrzej Śniadecki. Involved with the Philomaths, a secret student organisation dedicated to Polish culture and the restoration of Poland's independence, he was a close friend of Adam Mickiewicz. In 1823–24, during the investigation and trials of the Philomaths, Domeyko and Mickiewicz spent months incarcerated at Vilnius' Uniate Basilian monastery.

After participating in the November 1830 Uprising, in which Domeyko served as an officer under General Dezydery Chłapowski, in 1831 Domeyko was forced into exile in order not to face Russian reprisals.

In 1838 Domeyko left for Chile. There he made substantial contributions to mineralogy and the Technology of mining, studied several previously unknown minerals, advocated for the civil rights of the native tribal peoples, and was a Meteorologist and ethnographer. He is also credited with introducing the metric system to Latin America.

He served as a professor at a mining college in Coquimbo (La Serena) and after 1847 at the University of Chile (Universidad de Chile, in Santiago), of which he was rector for 16 years (1867–83).

Domeyko gained Chilean citizenship in 1849, but declared at the time that "I may now never change my citizenship, but God grants me hope that wherever I may be—whether in the Cordilleras or in [the Vilnius suburb of] Paneriai—I shall die a Lithuanian." The term "Lithuanian" at that time, however, designated any inhabitant, whatever his ethnicity, of the territories of the former Grand Duchy of Lithuania.

In 1884 Domeyko returned for an extended visit to Europe and remained there until 1889, visiting his birthplace and other places in the former Commonwealth, as well as Paris and Jerusalem.

In 1887 he was awarded an honorary doctorate by the Jagiellonian University, in Kraków.

In 1889, soon after returning to Santiago, Chile, Domeyko died.

In 1992, a plaque in Spanish and Polish was placed on a building at Krakowskie Przedmieście 64, in Warsaw, Poland, commemorating the "distinguished son of the Polish nation and eminent citizen of Chile."

Also in 2002, a 200th-birthday plaque honoring him was placed in the entry gate to Vilnius' Uniate Basilian monastery, where he and Adam Mickiewicz were held in 1823–24 during the investigation and trials of the Philomaths.

Domeyko was born at a manor house located within the then Russian partition of the former Polish-Lithuanian Commonwealth, at Niedźwiadka Wielka (Belarusian: Мядзьведка — Miadzviedka) Manor (Bear Cub Manor) near Nieśwież (Nesvizh), Minsk Governorate, Imperial Russia (now Karelichy district, Belarus). The Domeyko family held the Polish coat of arms Dangiel. His father, Hipolit Domeyko, who was President of the local land court (Polish: sąd ziemski), died when Ignacy was seven years old; his uncles then served as his guardians.

In 2015 a Belarusian climber Pavel Gorbunov placed a memorial plate on the top of Cerro Kimal in Cordillera Domeyko.