On December 26, 1240, Ildebrandino Cacciaconti, the then podestà of Siena, signed a decree imposing a tax on citizens of Siena who rented rooms to students of the local "Studium Senese". The money from this tax went to pay for the salaries of the maestri (teachers) of this new studium.The studium was further supported when, in 1252, Pope Innocent IV declared both its teachers and students completely immune from taxes and forced labour levied on their person or property by the city of Siena. Moreover, the commune exempted teachers of law and Latin from military service and teachers of Latin were also excused from their duties as night watchmen. By the early 14th century, there were five teachers of Latin, logic and law and two doctors of natural sciences (medicine).
In 1321, the studium was able to attract a larger number or pupils due to a mass exodus from the prestigious University of Bologna when one of its students was sentenced to death by Bologna's magistrates for supposedly kidnapping a young woman. Partly at the instigation of their law lecturer Guglielmo Tolomei, the student body there unleashed a great protest at the Bolognese authority and Siena, supported by generous funding from the local commune, was able to accommodate the students resigning from the Studium Bolognese.
The studium of Siena was eventually promoted to the status of "Studium Generale" by Charles IV, shortly after his coronation as Holy Roman Emperor in 1355. This both placed the teachers and students under the safeguard of the imperial authority (protecting them from the local magistracy) and also meant that the licences (licentiae docendi) granted by the university were licences ubique docendi. These licences entitled the person receiving them to teach throughout Christendom.
The Casa della Sapienza was built in the early 15th century as a center combining classrooms and housing for those enrolled in the Studium. It had been proposed by bishop Mormille in 1392, was completed twenty years later, and its first occupants took up residence in 1416. Room and board in 1416 cost fifty gold florins for a semester.
By the mid-14th century, Siena had declined as a power in Tuscany, eclipsed by the rise in power of Florence, who defeated the Republic of Siena in 1555. The city authorities, however, successfully asked the Medici (the hereditary dukes of Florence at the time) to preserve the academy. Francesco and later Grand Duke Ferdinando I, reforms were made with new statutes and new preogatives. The post of Rettore(Rector), elected by students and city magistrates, was also instituted.
In 1737, the Medici line became extinct and the rule of Tuscany passed to the French House of Lorraine. In this period, the Tuscan economist Sallustio Bandini, seemingly determined to "improve the intellectual stimulation of his native Siena" solicited scholarships from rich patrons for the university and also set up a large library, which he eventually bequeathed to the university.
In 1808, when the Napoleonic forces occupied Tuscany, they eliminated the Studium Senese and the doors of the University were not opened again until after the defeat of Napoleon and the restoration of Ferdinand III as the Grand Duke of Tuscany.
After the Second Italian War of Independence in 1859 and its aftermath, Tuscany and with it Siena were controlled by the Kingdom of Sardinia, which was to become the Kingdom of Italy. The Sienese academy eventually recovered from the unrest, thanks to initiatives by the city's private enterprises and a series of legislative acknowledgements that boosted the reputation of the School of Pharmacy and that of Obstetrics (and consequently the School of Medicine itself) while the old hospital Santa Maria della Scala was transformed into General University Hospital.
In 1892, the Minister of Public Education, Ferdinando Martini, launched a proposal aimed at suppressing the Sienese academy’s activities. Siena perceived this as a declaration of war and was backed immediately by a general tradesmen’s strike, the intervention of all of the town’s institutions and by a genuine uprising of the population – all of which induced to minister to withdraw the project. Having escaped this danger, the town went back to investing its resources in the university setting up new degrees and new faculties. The bank Monte dei Paschi di Siena financed the construction of the biology department.
The 20th century witnessed the growth of the University of Siena, with the student population escalating from four hundred between the wars to more than 20,000 in the last few years.
During the start of the academic year, on November 7, 1990 the Sienese academy celebrated its 750th anniversary.