Merli studied in Milan, with Carlo Negrini and Adelaide Borghi. In 1914, he won second prize at a singing competition in Parma, after Beniamino Gigli. He made his debut at La Scala in 1916, as Alvaro in Spontini 's Fernand Cortez.
Merli sang widely in Italy and South America and toured Australia in 1928 with other La Scala singers. He appeared at the Royal Opera House in London, from 1926 to 1930, where he was the first Calaf (Turandot) there. He made his debut at the Palais Garnier in 1935, as Pollione in Norma. His only season at the Metropolitan Opera in New York, debut on March 2, 1932, as Radames (Aida) was not successful because of poor health.
Merli was renowned for his vocal brilliance, penetrating tone and incisive diction. These qualities enabled him to tackle a wide operatic repertory, ranging from bel canto works to verismo. Famous operas that he appeared in included Guglielmo Tell, Il pirata, Il trovatore, Andrea Chenier and Pagliacci. He became world famous for his portrayals of Verdi 's Otello, and Calaf in Puccini 's Turandot, of which he left a 1938 complete recording, opposite Gina Cigna and Magda Olivero. He also made numerous recordings of opera arias. These, like the complete Turandot, have been re-issued on CD.
Merli also created the title role in Respighi 's Belfagor in 1923. He retired from the stage in 1948.