The stadium construction started in 1925 in the Milanese district of San Siro, which gave its original name. The idea to build a stadium in the same district of the horse racing track, belongs to the man who then was the president of A.C. Milan, Piero Pirelli. The architects designed a stadium only for football (there is no athletics track in it). The inauguration was on 19 September 1926, when 35,000 spectators saw Inter defeat Milan 6-3. Originally the ground was home and property of AC Milan, later Internazionale became tenants and the two have shared the ground ever since. Although Giuseppe Meazza played for both Internazionale and AC Milan, he enjoyed more success at Inter and is more favoured by the Inter faithful; as a result, Milan fans favour the term San Siro for the ground. Fox Soccer Channel has often referred to the stadium as Stadio Giuseppe Meazza di San Siro when airing replays of past Milan home matches.

As well as being used by Milan and Inter, the Italian national side also plays occasional games there and it has also been used for the 2000/01, 1969/1970 and 1964/65 Champions League/European Cup finals. The stadium was also used for UEFA Cup finals when played over home and away legs but has never featured since the competition changed to a single final structure in 1997/98.

The stadium underwent further renovations for the 1990 World Cup with $60m being spent, bringing the stadium up to standard. As part of the renovations, the stadium became all seated, with an extra tier being added to 3 sides of the stadium. This entailed the building of 11 concrete towers around the outside of the stadium. Four of these concrete towers located at the corner to support a new roof which has distinctive protruding red girders.