The sanctuary is in cruciform, or cross-shaped, design with a long center section and two transepts, or cross pieces. At the point of the crossing is a high area called the Lantern. The Chancel is the raised area in the front where Worship is led on Sunday mornings. Throughout the sanctuary are architectural details embedded in the stone columns, incorporated into the "transom" part of the stained glass windows, and carved into the pews, similar to the patterns carved into the stone arches at the entrance to the church.

The banners hanging on either side of the Chancel were commissioned in celebration of the 100th anniversary of the congregation's location on this corner in the Central West End in 1996, and they were made by St Louis quilting artist Marianne Oxboe. The banner on the left depicts "the living cross," a symbol of the involvement of the church in the community. The banner on the right, a series of different sized circles, is a representation of "the ever-changing world" to which the church must respond. The paraments on the pulpit (left) and lecturn (right) continue the colors and motifs of the bigger banners. There are also special banners for the various church seasons of Advent, Christmas, Lent, and Easter.

The long, tiled aisle makes the church a popular location for weddings, and the pipe organ, a four manual 60 rank Schantz, was installed in 1965. It contains 3,304 pipes, ranging in size from just a few inches to 16 feet long.

The room between the sanctuary and the front door is called the Narthex, decorated by photographs of the church's life over the past century. Theodore Roosevelt attended worship here while visiting the World's Fair in 1904, and General Dwight Eisenhower and Mrs. Eisenhower attended during the presidential campaign of 1952. The room between the sanctuary and Niccolls Hall is called the Session Room and includes pews and an ornate chair that date to the late 1800s when the congregation worshipped in its Lucas Place location.