In 1168, in response to the aggression of Emperor Frederick Barbarossa, the leaders of Milan, Cremona and Piacenza, established a new town in order to discomfit Frederick's ally Pavia. Seeking support for their undertaking, they sent ambassadors to Pope Alexander III in 1170, announcing that they had named the new city in his honor and begging for his support. They offered the city to the Papacy to be forever the vassal of the Holy Roman Church. Alessandria was made a see in 1175 by Pope Alexander III, with territory removed from the diocese of Acqui. The clergy of Acqui objected, of course, and, at a vacancy in the bishopric of Alessandria, they sometimes attempted to elect a bishop of their own; the Papacy was therefore faced with the need to sort out conflicts between the Chapter of Alessandria and the Chapter of Acqui. In a Brief of 30 January 1176, he declared that he had selected Alessandria's first bishop, though he did so without any prejudice to the rights of the Chapter for the future to elect their bishop, just as the other suffragans of Milan did. The diocese was suppressed in 1213 by Pope Innocent III, due to their support of the Emperor Otto IV. It was restored in 1240 by Pope Gregory IX as part of his strategy to defeat Frederick II. The territory of the diocese of Acqui was united with that of Alessandria until 1405, when Acqui again received its own bishop. The diocese was suppressed in 1803, as part of the effort on the part of the Papacy to regularize the situation after the liquidation of the "Cisalpine Republic", which had been created in northern Italy by General Napoleon Bonaparte. Alessandria was re-established as independent in 1817. It was vacant from 1854 to 1867.
The diocese has 75 parishes, all within the Piedmontese province of Alessandria. In 2012, there was one priest for every 1,641 Catholics. ;Alessandria ;Alluvioni Cambiò ;Bassignana ;Borgoratto Alessandrino ;Bosco Marengo ;Capriata d’Orba ;Carentino ;Casal Cermelli ;Castellazzo Bormida ;Castelspina ;Felizzano ;Frascaro ;Frugarolo ;Gamalero ;Isola Sant’Antonio ;Montecastello ;Oviglio ;Pasturana ;Pecetto di Valenza ;Pietra Marazzi ;Piovera ;Predosa ;Quargnento ;Rivarone ;Solero ;Tassarolo ;Valenza
