Like a medieval European cathedral, the exterior of Altoona's cathedral took many years to complete, and its interior stood unfinished for twenty-eight additional years while services were held amid bare brick and rough concrete walls. The building sits on a rise and is raised further on a basement, making it visible for miles. The domed crossing gives the massive Indiana limestone cathedral the appearance of a state capitol. Forty-eight stone steps, separated into smaller groups by broad terraces, lead to the entrance portico with its six fluted Ionic columns in antis supporting a balustrade. Above this, the central pedimented portion over the nave is reminiscent of the church of S. Maria Novella in Florence, while the dome incorporates elements from St. Peter's in Rome and Filippo Brunelleschi's cathedral dome in Florence. Philadelphia architect George Ignatius Lovatt (1872–1958) had completed dozens of churches nationally by the mid-1920s, most of which were in Philadelphia and Delaware.

The cathedral's cruciform plan has three aisles separated by six massive piers on each side, and a dome at the crossing of transept and nave. A continuing program of embellishment and remodeling gives the cathedral its evolutionary quality: the exterior and interior obviously date from different eras. The pews and much of the interior, dedicated in 1960, were designed by Alfred Reid of Pittsburgh, using a modern vocabulary in contrast to the historical appearance of the exterior. Since 1986, several stained glass windows by Hunt Studios of Pittsburgh have replaced earlier colored and frosted glass windows. In addition, engraved glass panel doors by Baut Studios of Pennsylvania have been installed on the facade.