The Franciscans, often called the Barfüsser or «barefooted ones», settled in Basel in 1231. In 1250 the Bishop of Basel gave them some land alongside the city wall on which to build, and by 1256 they had erected a monastery complete with a church. Just a few years later this was torn down and rebuilt (1275–1309). The second Barfüsserkirche was built further to the north, and at 80 metres long it was significantly larger than the first. It stood on a 2-metre-high mound of gravel, moreover, which is why the remains of the first church are located in the basement of today’s church.

When Basel embraced the Reformation in 1529, the monastery passed into the hands of the city. The cemetery became the Barfüsserplatz, while the monastery itself was used to house parts of the hospital, the poorhouse and schools, and the cloister was repurposed as a lunatic asylum. The church remained a Protestant house of worship until 1794, even after the choir was boarded up to allow it to be used as a granary. From 1795 it served as a warehouse and from 1799–1815 it was used to stockpile salt, which explains how some 300 tonnes of salt came to seep into the floor. Demolition of the monastery began in 1843, and from 1845–1865 the site was the location of Basel’s customs warehouse.

There were various plans for the church – either it was to be torn down in part or in full, or it was to be converted into a school or a swimming pool, a library or an archive, a market hall or a gym – none of which was realized. In the meantime, the building was used as a post office, dairy market, pawnshop, glove shop and, as before, as a warehouse. In the absence of a plan and someone to take responsibility for it, the church fell into disrepair. The city proposed it as a location for the new Swiss National Museum it was bidding for in 1888, but after losing out to Zurich was once again left with a church without a mission.

Basel eventually decided to use the church as premises for its new Historical Museum and from 1890–1894 had it converted for that purpose. By 1964 the salt corrosion had become so serious that radical renovation work was essential. Making a virtue of a necessity, the city furnished the church with a lower level and so provided additional exhibition space for the museum.