The University Place Presbyterian Church was officially established in 1845 by members of the Duane Street Presbyterian Church who wished for a community further uptown. With more than $60,000 in donations (or subscriptions), the new parish purchased a plot at the corner of University Place and 10th Street from the managers of Sailors' Snug Harbor who owned this and much of the surrounding acreage. The parish commissioned famed architect Richard Upjohn to design their new home. Rendered in an English Gothic style with soaring spire, the church was dedicated in June 1845.

In the ensuing decades, the once wealthy surrounding neighborhood began to decline as well-to-do New Yorkers moved further uptown. The church merged with Mercer Street Church in 1870 while continuing to use this edifice. Further financial struggles due to declining membership necessitated the 1918 merger of this church and the Madison Square Presbyterian into the nearby Old First Presbyterian Church on Fifth Avenue and 12th Street.

In 1927 the old church was razed and in its place, the Devonshire House, a 14-story apartment building, was erected the following year.