While there are records of a church standing in the same site as Seton Collegiate Church dating back to the 13th century, the current building was finished in the late 15th century under the auspice of the Seton family. The Setons built their palace in the proximity of the old church and provided funding to turn the existing sanctuary into a collegiate in 1492.

As a collegiate church, up to six men at a time were educated and ordained as priests by a leading provost in Seton, under the caveat that they would constantly pray in favor of the Setons. Following the Reformation, with mass being abolished throughout many Scottish churches, Seton was reformed into a private family chapel.

With the Setons having sided with the losing Jacobites in the early 18th-century uprising, the church was eventually abandoned until its renovation by order of its new owner Lord Wemyss in 1878. In 1920, the building and surrounding area, including the ruins of the priests' living quarters but excluding the privately-owned Seton Palace, were declared a Historic Monument of Scotland.

Update as of July 2022: The church is temporarily closed.