Alessandria was founded in 1168 with a charter as a free comune; it was sited upon a preexisting urban nucleus, to serve as a stronghold for the Lombard League, defending the traditional liberties of the communes of northern Italy against the Imperial forces of Frederick Barbarossa.

A legend (related in Umberto Eco's book Baudolino, and which recalls one concerning Bishop Herculanus’ successful defence of Perugia several centuries earlier) says it was saved by a quick-witted peasant, Gagliaudo: he fed his cow with the last grain remaining within the city, then took it outside the city walls until he reached the Imperial camp.

[5] In 1450 Alessandria passed with their possessions to the Sforza, following the career of Milan, until 1707, when it was ceded to the House of Savoy and henceforth formed part of Piedmont.

Alessandria was the first capital of an Italian province to be governed by a Socialist: the clockmaker Paolo Sacco was elected mayor on 25 July 1899.

Owing to its marshalling yard and the bridges on the Tanaro and Bormida, Alessandria was a strategic military target during World War II and was subjected to intense Allied bombing (especially during Operation Strangle), the most serious being the raids of 30 April 1944, with 238 dead and hundreds wounded, and 5 April 1945, with 160 deaths, among them 60 children from the children's asylum in Via Gagliaudo.

Altogether, 559 people were killed by air raids on Alessandria, which destroyed or badly damaged a thousand buildings.

The first known Jews in Alessandria, named Abraham (son of Joseph Vitale de Sacerdoti Cohen) opened a loan bank in or about 1490.

It is also a junction for six other lines, to Piacenza, Novara, Pavia, Cavallermaggiore, Ovada and San Giuseppe di Cairo, respectively.