Archaeological discoveries in Hardinxveld-Giessendam indicate that the area of South Holland has been inhabited since at least ca. 7,500 years before present, probably by nomadic hunter-gatherers. Agriculture and permanent settlements probably originated around 2,000 years later, based on excavations near Vlaardingen. In the classical antiquity, South Holland was part of the Roman Province of Germania Inferior, and the border of the Roman Empire ran along the Old Rhine and reached the North Sea near Katwijk. The Romans built fortresses along the border, such as Praetorium Agrippinae near modern-day Valkenburg, Matilo near modern-day Leiden, and Albaniana near modern-day Alphen aan den Rijn. A city was founded near modern-day Voorburg, Forum Hadriani. It was built according to the grid plan, and facilitated a square, a court, a bathhouse and several temples.
After the departure of the Romans, the area belonged to the Frisian Kingdom, after which it was conquered by the Frankish king Dagobert I in 636. In 690, the Anglo-Saxon monk Willibrord arrived near Katwijk and was granted permission to spread Roman Catholicism by the Frankish king Pepin II. He accordingly founded a church in Oegstgeest, after which the entire area was gradually Christianised. The area was appointed to East Francia in the Treaty of Verdun in 843, after which the king granted lands to Gerolf, who had helped him claim the lands. This was the birth of the County of Holland. Gerolf was later succeeded by Dirk I, who continued to rule Holland under the Frankish king. In 1248, count William II ordered the construction of the Ridderzaal, which was later finished by his son and successor Floris V.
The first city in South Holland to receive city rights was Dordrecht, which did so in 1220. The city retained a dominant position in the area until it was struck by a series of floods in the late 14th century. The same century also saw a series of civil wars, the Hook and Cod wars, concerning the succession of count William IV. Both his daughter Jacqueline and his brother John, the latter supported by Philip the Good, Duke of Burgundy, claimed the throne. The conflict ended in 1490, with John victorious.
Overall, the area of South Holland remained largely agrarian throughout the late Middle Ages. This changed around 1500, when Holland became Europe's most urbanised area. During the Eighty Years' War, the area of South Holland was the scene of the Capture of Brielle, the Siege of Leiden and the assassination of William the Silent.
The United Netherlands declared their independence in 1581, and Holland quickly emerged as the country's dominant province, with important trading cities such as Leiden, Delft, Gouda and Dordrecht. In 1575, the Netherlands' first university was founded in Leiden by William the Silent. The Hague, which had originated around the castle of the counts of Holland, became its new political centre. Both the States of Holland and the States General seated in the Binnenhof. The Dutch Golden Age blossomed in the 17th century. The south of Holland, back then often referred to as the Zuiderkwartier (literally "South Quarter"), was the birthplace and residence of scientists such as Antoni van Leeuwenhoek and Christiaan Huygens, philosophers such as Baruch Spinoza and Pierre Bayle, and painters such as Johannes Vermeer, Rembrandt van Rijn and Jan Steen.