The patron saints of Acqui Terme are Saint Guido and Saint Maiorinus, celebrated on 11 July. Saint Guido, bishop of the town, completed the works on the cathedral of Santa Maria Assunta in the 11th century, consecrating it in 1067, and founded two monasteries in the town, one for women near Santa Maria de Campis and one for men near the old early-Christian church of San Pietro; the cathedral, a Romanesque Latin-cross building, still preserves today his Baroque altar and the Annunciation triptych by the Catalan painter Bartolomeo Bermejo. Saint Maiorinus, on the other hand, was the town's first bishop, perhaps in the late 4th century: it was precisely the presence of the thermal baths, still in use in the Gothic and Lombard periods according to the accounts of Cassiodorus and Paul the Deacon, and of an episcopal seat that ensured Acqui's survival during the difficult early Middle Ages, when many other towns of southern Piedmont were abandoned.
Visible from the Carlo Alberto bridge over the Bormida river are still today the remains of the Roman aqueduct, with its 15 surviving pillars and 4 arches. From 1306, when the House of Aleramici died out, the marquisate of Acqui passed to the Palaiologos, heirs of the Aleramici through the female line, who returned there several times until their own extinction in 1533, when the whole of Monferrato passed to the Dukes of Mantua: the Castello dei Paleologi still dominates the town's historic centre today.
