Born in Grotte di Castro, Carlo Salotti attended the seminary in Orvieto before going to Rome, where he studied at the Pontifical Roman Athenaeum S. Apollinare and the Royal University.

While performing his pastoral ministry in Rome until 1912, Salotti became a professor at his alma mater of the Pontifical Roman Athenaeum S. Apollinare in 1902.

On 30 June 1930, Salotti was appointed Titular Archbishop of Philippopolis in Thracia by Pope Pius XI, and Secretary of the Congregation for the Propagation of the Faith, where he served under Cardinals van Rossum and Pietro Fumasoni Biondi, and rector of the Pontifical Urbaniana University four days later, on 3 July.

He received his episcopal consecration on the following 6 July from Cardinal Willem van Rossum, CSsR, with Bishops Luigi Olivarès, SDB, and Giovanni Rosi serving as co-consecrators, in the basilica of Sacro Cuore di Gesù a Castro Pretorio.

On 14 September 1938, Salotti was named Prefect of the Congregation of Rites and participated in the 1939 papal conclave that selected Pope Pius XII, who advanced him to Cardinal Bishop of Palestrina on 11 December 1939.