The compact historic center welcomes with a regular urban layout of wide parallel streets intersected by narrow alleys: an immediate similarity with military camps. This is exactly how the Republic of Venice, established in Friuli in 1420, wanted the development of Gradisca, founded in 1479, which was supposed to allow easy movement of troops at the borders of its possessions, threatened by the Turks. The city walls, twenty meters high compared to the underlying moat, were equipped with seven circular watchtowers and two entrance gates.

From that period is the Casa dei Provveditori, residence of the representatives of the Venetian government, with a typical massive late 15th-century structure and a barbican to reinforce the corner, while the rectangular trabeated windows of the facade and the wrought iron balcony are from the 18th century. From the 15th century also survive the vaulted ceilings of the ground floor and the two arched bifora windows on the northern side of Palazzo Coassini, formerly Palazzo del Fisco, whose facade was redone in the 1700s, and the church of the Beata Vergine Addolorata, built between 1481 and 1498. Transformed into a warehouse by Napoleonic decree in 1810, it lost sacred objects, the grand main altar, and the side altars, sold by the French, while the statue of the Madonna Addolorata was saved. The church was reconsecrated in 1850 after Francesco Giovanni and Anna Coassini repurchased it and donated it to the city, but it was again a warehouse during the First World War and even set on fire during the events of nearby Caporetto, to be rebuilt and restored in 1921-3. The Turkish threat that led to the fortified center of Gradisca did not diminish the power of the Serenissima. It was Maximilian I of Habsburg who did so in 1511, initiating a phase of tensions with the Venetian republic that culminated in the Gradiscan wars (1615-17). The village was so damaged that it was sold in 1647 by the Austrian Empire, engaged in Germany in the Thirty Years' War, to the Styrian nobles Eggenberg. In this period, which ended in 1717 due to the lack of male heirs with the return to the hands of the Habsburgs, the local ruling classes achieved significant autonomy and the center shifted from military to administrative and economic. The area was known as a true granary, renowned for red wines, silk processing and trade, and smuggling of all kinds. 

By the end of the 1600s, all the most representative noble palaces had been built: the imposing Palazzo de’ Comelli-Stuckenfeld with its squared portal topped by a balustrade overlooking an arched French door concluded by an additional entablature, and in its style Casa de’ Portis, Casa de’ Salamanca, and Casa Wassermann, followed in the early 1700s by Casa de’ Brumatti, Casa Brumat, Casa Spangher, and Casa Ciotti. Also dating back to the 17th century, both almost intact, are the slender Loggia dei Mercanti, with three rusticated arches, and the Palazzo del Monte di Pietà, with elegant stringcourse frames in white Carso stone and a keystone portal topped by a large baroque canopy with a sculpted Pietà. Between the early 1600s and 1725, the current Palazzo Torriani was formed, the most representative building of Gradisca, a stronghold of Venetian culture with its Palladian design featuring a central body and symmetrical side wings. Today it houses the town hall, the Galleria d’Arte Contemporanea Spazzapan, and the Museo Civico. Also dating back to the mid-1600s is the austere Casa Toscani, which preserves, overlooking the inner courtyard, a double loggia with the second order of arches lowered, very similar to typical Styrian and Carinthian solutions of the time, and Palazzo de Fin-Patuna already transitioning from baroque to rococo.

In 1754 Gradisca experienced a setback: Empress Maria Theresa of Habsburg decided to unite the counties of Gorizia and Gradisca. The latter was no longer strategic because the empire had eroded the Serenissima and extended over much of northern Italy. This change authorized the village to demolish a section of the walls in which it had lived for centuries. The green “Spianata” thus created became the center of the town's social life.