The road that today constitutes the street was laid by Francisco Pizarro when he founded the city of Lima on January 18, 1535. This straight line formed the colonial road to Callao and at its mouth was one of the arches of the Walls of Lima, the Portada del Callao, built in 1797.
In 1862, when a new urban nomenclature was adopted, the road was named jirón Moquegua, after the Department of Moquegua. Prior to this renaming, each block (cuadra) had a unique name:
Block 5: León de Andrade, after José de León y Andrade, who lived there during the 18th century.[5]
Block 6: Animitas, after an establishment where alms were collected for the "souls in purgatory." This street was opened towards the beginning of the 17th century.[6]
Block 7: Callao, since, being the last one, the path to the port of Callao began there. In 1797, Viceroy Ambrosio O'Higgins ordered the construction of the Portada del Callao, forming a promenade, later called Malambito (a name that still persists) because it was smaller than the Malambo promenade that existed in the northern neighbourhood of San Lázaro.[7]
During the 1980s, the street was the birthplace of Bakom, a martial art based on different techniques from Lima's street-fighting history.[8]
On the morning of August 22, 1991, three car bombs were detonated by members of the Túpac Amaru Revolutionary Movement, a terrorist organisation, who were distributed into three groups. Two of them, belonging to Electrolima, were located on the seventh block of the avenue, while the other, belonging to the Compañía Peruana de Teléfonos, was located on nearby Guillermo Dansey Avenue. A street vendor, who witnessed the action, entered the Dos de Mayo school alerting the students of the imminent attack, with the bombs exploding during their evacuation. In total 34 people were injured, including children, 30 commercial establishments were damaged, and the attackers fled towards the Plaza Dos de Mayo, Avenida Emancipación and Avenida Tacna.[9]
In 2020, an explosive artifact was detonated in front of a shoe store, causing minor damages to its façade.[10]