Holy Spirit Chapel is one of the smaller but most beloved chapels at the Cathedral. The chapel is always reserved for quiet and personal prayer.

The intricately carved wooden reredos behind the altar features a serene vision of heaven and the descent of the Holy spirit. The painted oak panels, completed in 1936, are the work of noted American artist N.C. Wyeth. Numerous doves — the symbol of the Holy Spirit — appear throughout the chapel, including in the wrought iron gates and grilles that enclose the chapel.

The single stained glass window depicts Jesus meeting the Samaritan woman at the well and uses colors inspired by fire, a further reference to the Holy Spirit, which is traditionally depicted by a flame.