Siena became an important banking centre in the 13th century but was unable to compete with its rival, Florence.  The imperial cause declined, and the popes imposed economic sanctions against Siena's Ghibelline merchants. Soon afterward, Siena itself turned Guelf, and the Ghibelline nobility lost its share of power. The city suffered from wars and famines and from the general economic decline that afflicted Italy in the early 14th century, and it was also
devastated by outbreaks of the Black Death, which began in 1348. 

Siena endured between 1355 and 1559 the two most troubled centuries in its history: a long period of economic and demographic decline, of social conflict, and of increasing. instability and tension in political life. Unstable régime followed unstable régime; in one disastrous year, 1368, the city's constitution was actually changed 4 times in an attempt to accommodate its contending power groups, while, even more remarkably, the government structures of
Siena were actually reformed 10 times between 1525 and 1552. 

Externally this was also a period of incessant, purposeless and profitless warfare, although foreign warfare was less damaging to the economy than were the numerous visitations of marauding mercenary companies throughout the 14th and 15th centuries. This was, in addition, a period in which the determination of the Florentines to conquer Siena became increasingly obvious. The Sienese attempted numerous solutions to their difficulties, and in 1399, despite the strength of the city's communal traditions, even resorted to the expedient of surrendering their city into the hands of Giangaleazzo Visconti of Milan. Visconti rule of the city lasted until 1404. A more positive solution was the development of the system of governement by a balia which, in Siena, became converted into a permanent magistracy and effectively replaced the traditional communal councils. 

One feature of Siena's political life at this period has always provoked comment. This was the system of monti or ordini whose very existence seemed to institutionalize civic strife. Each member of the ruling élite of Siena was a member of one of the city's 5 "monti", and each "monte" competed with the others for a monopoly of power in Siena.  Attempts were made to devise some form of power-sharing by which the monti could be brought to cooperate together, and these efforts were not always unsuccessful. Indeed, the periods of internal peace in Siena were ones when such coalitions worked well. This is the light in which we should see the period 1458-63, the pontificate of Pius II, when Siena effectively became a papal dependency. In 1487 an exiled aristocrat, Pandolfo Petrucci, seized power and ruled with brutal tyranny through a period of French and Spanish invasions until his death in 1512. His regime was continued by his family until 1524. This so-called "signoria of the Petrucci" can best be understood as the most successful power-sharing exercise of the period, in which the Petrucci acted as peculiarly effective chairmen of the various coalitions by which Siena was governed. 

In the early 16th century, as the economic decline of Siena accelerated, and the position of her ruling élite weakened in consequence, the successful creation of such coalitions became difficult. Siena was constantly torn by party strife and civic turmoil and this turbulence created a kind of political vacuum in the centre of Italy from which the French hoped to profit. Charles V was forced to respond to this French threat by taking an interest in the city, and in in the 2nd quarter of the century Spanish influence in Siena became increasingly obvious. After 1530 a garrison of Spanish troops looked as if it would guarantee the city's loyalty, but to make certain Charles V decreed that a fortress should be built in Siena. This action forced the Sienese into open rebellion in 1552, and the Spanish were driven from the city.

With sporadic French assistance, the Sienese tried to preserve their independence for the next 3 years in what has become famous as an heroic struggle against the combined forces of Spain and Cosimo I de' Medici, but in 1555 Siena was starved into surrender, although fighting continued in the Sienese contado for another 4 years. Siena was governed directly by the Spanish until 1557, when it was sold to Cosimo, whose possession of the city was confirmed by the Peace of Cateau-Cambrésis. After 1559, therefore, the history of Siena followed that of  he Grand Duchy of Tuscany. In 1861 Siena, together with the rest of Tuscany, was absorbed into the new Kingdom of Italy.