Dolenjska was settled early on and is well known for its Hallstatt (early Iron Age) ruins, especially near Stična, Šmarjeta and Novo Mesto. The Romans made the area part of the province of Upper Pannonia (Pannonia Superior) and crossed it with roads.

In the Middle Ages, the population clustered around the many castles along the river, such as those at Žužemberk and Otočec, while monasteries sprung up at Stična, Kostanjevica na Krki and near Šentjernej.

Dolenjska declined after the Middle Ages and progress only came in the late 19th century when a railway line linked Novo Mesto with Ljubljana.