Leon Battista Alberti designed Sant'Andrea in 1470 as the greatest Renaissance church north of Rome — the first to fully break with Gothic tradition and return to Roman monumental forms. The triumphal arch façade, barrel-vaulted nave without side aisles, and coffered ceiling were all radical departures from contemporary church architecture, and deeply influential. The church was also the first to use a giant order of pilasters, a device Michelangelo and Palladio would later adopt widely.
Inside, the chapels lining the nave were frescoed by local masters over the following centuries. Mantegna himself is buried in the first chapel on the left, where a bronze self-portrait hangs. The octagonal crossing under the dome provides a moment of spatial drama after the long nave. The hidden bas-relief of a hare on the main portal — part of the Gonzaga emblem — has been rubbed smooth by visitors seeking good luck for centuries; finding it is a minor Mantuan game.