Cesarini was born in Senigallia, near Ancona, in the Italian region of Marche, but when he was only a few months old he and his family emigrated to Buenos Aires, in Argentina. In his early career he played for several clubs around the Buenos Aires area, during the amateur era in Argentine football, most notably Chacarita Juniors. in the 1933–34 Serie A Cesarini was signed by Italian giants Juventus in 1929, he made his debut against S.S.C. Napoli on 23 March 1930: the game ended in a 2–2 draw. He went on to win five league championships in a row with the club. In 1936 he returned to the professionalised Argentine league where he won two championships with River Plate. This excellent River Plate team included two young players who would become legends of the game Adolfo Pedernera and José Manuel Moreno. The team was coached by the Hungarian Emerico Hirschel who had a big influence on Cesarini and his teammate Carlos Peucelle which would be put to use in the 1940s as they took charge at the club.
After retiring as a player, Cesarini went on to become a football manager. He coached a number of clubs in Argentina including both Boca Juniors and River Plate. With River he coached one of the greatest teams of all time. From 1941 to 1947 this River Plate team achieved legendary status: Cesarini was coach from 1941 to 1944 when the level of football was such that they became known as La Maquina ; the forward line of Moreno, Pedernera, Munoz, Labruna and Lousteau is considered to this day to be the greatest seen in South America. River won Argentine league titles in 1941, and 1942 under La Biblia del fútbol as Cesarini became known for his authority on all matters pertaining to the sport. He returned to Italy to coach Juventus where he led a team including Sivori, Charles and Boniperti to Serie Asuccess. In the mid sixties he started the underage club of Pumas today one of the top clubs in Mexico. Between 1967 and 1968, he coached the Argentina national team.
The Italian expression zona Cesarini was originated as a reference to Renato Cesarini, who often scored decisive goals during the last minutes of the match. This expression is still in use today in Italian football and it designates a goal that is scored in the final minutes of a match, namely in zona Cesarini.
Cesarini has a football club and training academy in Argentina named in his honour, it was founded in 1978 by former members of the Argentina national team.
