The direct spark of the Thirty Years' War flared in Prague on 23 May 1618: Protestant nobles of Bohemia threw two Catholic imperial governors out of the windows of Prague Castle after the crown rejected their demands on religious rights. This Third Defenestration of Prague began what looked like a local revolt, but the fragile balance of the 1555 Peace of Augsburg and the Habsburg–Bourbon rivalry soon spread the war across the continent. The Bohemian revolt was crushed in 1620 at the Battle of White Mountain, the first major victory of the Catholic side.

The war escalated in phases. In 1625 King Christian IV of Denmark took up the Protestant cause and was defeated; in 1630 King Gustavus Adolphus of Sweden intervened with his disciplined army, breaking the imperial forces at Breitenfeld and Lützen (where he himself was killed). In 1635 France — although a Catholic kingdom — formally joined the Protestant side to break the Habsburg encirclement. This was the clearest sign that the war had ceased to be a confessional conflict and had become a struggle over the balance of power among Europe's dynasties. Mercenary armies looted villages; the 1631 Sack of Magdeburg became a symbol of civilian massacre.

The destruction suffered by the German-speaking lands was the heaviest seen in pre-modern Europe. In some regions population losses exceeded fifty percent — caused not only by battle but by epidemics, famine and displacement. For the total population loss historians usually give a range between twenty and forty percent; because the figures vary widely from region to region, no single precise number exists. Agriculture collapsed, mercenary armies drained local economies, and the population of many towns did not recover for decades. Brandenburg, Württemberg and Pomerania were among the worst hit.

The war ended in October 1648 with the treaties of Münster and Osnabrück, together known as the Peace of Westphalia. Its consequences were lasting: religion largely withdrew from interstate diplomacy, the Holy Roman Empire effectively dissolved into more than three hundred sovereign units, the independence of the Dutch Republic and the Swiss Confederation was formally recognised, and France emerged as the continent's new center of power. The Thirty Years' War is the war in which Europe learned the cost of trying to organise itself both around confessional lines and around a universal imperial model. After it, politics would be thought of not in terms of a shared truth but in terms of balanced relations among limited sovereign states.