Together with Amadeus, Italian comedian and television presenter Fiorello returned, after appearing as a regular guest in the previous edition, to cover the role of co-host.

[2] Alongside Amadeus and Fiorello, five co-hosts alternated during the five evenings: Matilda De Angelis, Elodie, Vittoria Ceretti, Barbara Palombelli and Beatrice Venezi.

[5][6][7] British supermodel Naomi Campbell was set to participate as co-host in the first evening, but due to restrictions imposed in United States for the containment of the COVID-19 pandemic, she had to give up the aforementioned role.

[11][12] On 7 October 2020, Rai Commission for Sanremo Music Festival 2021 announced a list of 961 acts, but only 61 artists coming from all Italian regions -excluding Basilicata and Valle d'Aosta- and from abroad were selected in the first phase.

Gaudiano, Folcast, Greta Zuccoli, Davide Shorty, Wrongonyou and Avincola were chosen as contestants of the Newcomers' section of the Sanremo Music Festival 2021.

The international television service Rai Italia broadcast the competition in the Americas, Africa, Asia, Australia and Europe.