Semen Hulak-Artemovsky was born in Horodyshche a city in present-day Ukraine (at the time a part of Imperial Russia) to the family of a priest, and went on to study at the Kiev Theological Seminary from 1835-1838. Having gained the attention of Mikhail Glinka, the young Semen was brought to the capital of the empire, St Petersburg, in 1838 to receive vocal training directly from Glinka, as well as entry into the Imperial Chapel Choir. The following year, Hulak-Artemovsky left to continue his studies in Italy. Towards the end of his stay in that country, he began performing opera in Florence. Upon his return to St. Petersburg in 1842, Semen Hulak-Artemovsky became a soloist of the Imperial Opera at the Imperial Bolshoi Kamenny Theatre, a position he held for 22 years. Additionally, he performed at the Bolshoi Theatre in Moscow from 1864 to 1865. He performed over fifty operatic roles during his career, including Ruslan in Glinka's Ruslan and Lyudmila, Masetto in Mozart's Don Giovanni, as well as Antonio and Lord Ashton in Donizetti's Linda di Chamounix and Lucia di Lammermoor.

A composer of operas, as well as vocal and instrumental music, Semen Hulak-Artemovsky composed his seminal work Zaporozhets za Dunayem in 1864, after completing the libretto in 1862.

His friendship with Taras Shevchenko began in the fall of 1838, after a chance meeting in St. Petersburg. The lifelong friendship continued during Shevchenko's incarceration and subsequent release, and was said to have strongly influenced Hulak-Artemovsky's view of the world. He dedicated his song A Maple Tree Stands Over The River (Ukrainian: Cтoïть явip нaд вoдoю, translit. Stoyit' yavir nad vodoyu) to Shevchenko.

Semen Hulak-Artemovsky died at the age of 60 in Moscow.