Domodossola was the chief town of the Lepontii when the Romans conquered the region in 12 BCE.
- Collegiate Church of St. Gervasius and Protasius
- Palazzo Silva. A 14th century building housing a civic museum containing Etruscan and Roman remains, fragments of Egyptian mummies and so on.
- Sacro Monte Calvario. One of the Sacri Monti (Sacred Mountains) of Piedmont and Lombardy, which together are a World Heritage Site.
- Sempioniano Civic Museum. A museum on the history of the Simplon Pass and the Simplon Tunnel.
- Street market. Sa 8am–3pm. Day trippers come from Switzerland just for this big market.