Speaking directly in front of European leaders at the Santa Maria Novella church in Florence, the Prime Minister is also expected to say successful negotiations are in the interests of everyone.
Nearly 600 years after the Council of Florence met to reunite the Latin and Greek churches, Mrs May will hope to heal rifts which seem to have deepened over the summer.
Joining her at the landmark church - which was consecrated in 1420 - will be Foreign Secretary Boris Johnson, Chancellor Philip Hammond and Brexit Secretary David Davis.
Home to works of art by notable Renaissance artists including Botticelli and Masaccio, Santa Maria Novella was also home to one of the earliest attacks on Galileo, accused of heresy in 1614 for claiming the earth moves around the sun.
According to Downing Street, Florence was selected for the speech because of the city's cultural and economic ties with the UK, and its "historical trading power.
Theresa May is expected to propose a two-year transition period which would see the UK pay Brussels a £18 billion so-called divorce bill and essentially keep the same rules in place for the customs union and the single market.