Huldrych Zwingli, independent of Luther, initiated the Protestant Reformation in Switzerland and gained support of the people of Zürich in the 1520s, when he was the main preacher at the Great Minster. The Reformation resulted in major changes in state matters and civil life in Zürich, spreading also to a number of other cantons. However, seven of the cantons remained Catholic and became the basis of serious conflicts that eventually led to the outbreak of the Wars of Kappel. The second war of Kappel, which affected Zürich to a greater extent than the first, was in 1531. The Catholic cantons achieved victory and implemented counter-reforms in some regions. The disagreements, which continued until the 18th century, caused a stagnation of the confederacy's foreign policy because the cantons couldn't find common ground.

The Zürich Bible, a bible translation based on that of Zwingli, was issued in 1531 and has been continuously revised thereafter. During the 1500s and 1600s, the Council of Zürich adopted an isolationist attitude, resulting in a second ring of imposing fortifications built in 1624. The Thirty Years' War which raged across Europe motivated the canton to build these defenses. However, the fortifications required a lot of resources, which were taken from subject territories without reaching an agreement in advance. The ensuing revolts were crushed brutally. In 1648, Zürich proclaimed itself a republic, shedding its former status of a free imperial city and modeling itself on city republics like Venice.

The French Revolutionary Wars caused much strife in Zürich. The city lost territories to Linth, Thurgau and Aargau in the Helvetic Republic (1798-1803). The French overran Switzerland in 1798, and as the confederacy collapsed, a republic was proclaimed that same year. Feudal rights and cantonal sovereignty were abolished. The cantons resisted revolutionary ideals, but also failed to unite effectively against the invaders. Eventually the republic collapsed due to financial difficulties.    
Furthermore, in 1799 the First Battle of Zürich ensued between France and the Second Coalition (Austria, Great Britain, Russia and the Ottoman Empire). French general Andre Massena had to give the city up to the Austrians and retreat. The French, however, regained control of Zürich in the Second Battle of Zürich that same year. Massena beat back the Austrians and Russians, and Russia withdrew from the coalition. In 1847, a war between the Catholic and Protestant cantons broke out, and only one later the federal constitution of Switzerland was adopted, making the country a federal state.