The eldest son of master stonemason Santini-Aichel, Jan Blažej, was born in Prague on February 3, 1677. The firstborn son was likely expected to follow in the footsteps of his father and grandfather, but a physical defect made it impossible for the boy to fulfill this task.

As the future proved, the boy rather outdid the hopes placed in him, although not in the art of stonemasonry. Santini apparently showed a significant artistic talent, as his father decided to have him trained as a painter and architect. There is speculation about the teacher of the young Jan Blažej, however, the fact that he was a properly trained painter and architect at the same time indicates the possibility that his teacher could have been Jean Baptiste Mathey, French architect working in Prague. This theory is supported by the fact that after Mathey's death, Jan Blažej took over most of Matthey's builders and cooperated with them. After completing his training, Santini set out on travels in 1696, which lasted over three years; there he made contact with the contemporary European architecture.

Although Jan Blažej designed and independently carried out constructions from 1700, we can only follow his work from a later period, roughly from the turn of 1702 and 1703. A very important step for his entire subsequent life was his acquaintance with the abbot of Zbraslav, Wolfgang Lochner, who is considered his first important client. Thanks to Lochner, Santini met other representatives of religious houses (primarily Cistercians and Benedictines). The abbots of these monasteries were the most important customers for the rest of Jan's short life. For example, in 1703, Santini started to work for the abbot of Sedlec, Jindřich Snopek, in 1706 for the abbot of Žďár, Václav Vejmluva, followed in 1707 by Plasy (abbot Eugen Tyttl), in 1710 by Kladruby (abbot Maur Fintzguth), etc. The environment of medieval monasteries and their abbots, who were mostly well-educated and purposeful personalities, became the inspiration for Santini's work. Of course, we can also find secular personalities among Santini's customers, but their list is undoubtedly shorter. Long-term work is documented only for the count Norbert Leopold Kolowrat-Libstein.

Although Santini worked in a not-so-distant past, it is not possible to clearly determine the exact number of buildings he designed during his lifetime. We are currently aware of approximately sixty buildings that can be attributed to him with certainty based on written sources. Most of them are buildings of above-average quality and about ten of them are considered among the absolute masterpieces of European architecture of their time.

Let us recall at least a few Santini's buildings that have survived to this day. The monastery church of the Assumption of Our Lady and St John the Baptist in Kutná Hora - Sedlec is a great example of a building where Santini carried out a major reconstruction of the originally Gothic cathedral (1703-1708). Today, this monumental building is unfortunately partially surrounded by industrial buildings and has suffered greatly from the height changes of the surrounding terrain. The monastery church of the Assumption of Our Lady in Kladruby near Stříbro, fundamentally rebuilt according to Santini's design in the years 1712-1726, is still a breathtaking piece of architecture that does not require further comments. Santini's initial project for the pilgrimage church of the Nativity of Our Lady in Křtiny was not fully implemented (moreover, the architect was already dead when its construction began), but the monumental appearance of the complex, well hidden in a valley near Brno, still enchants visitors. Among the secular buildings, we can mention, for example, the new building of the chateau Karlova Koruna in Chlumec nad Cidlinou. The castle, situated on a gentle hill, is a dynamic building with a central layout that attracts a lot of attention. The floorplan was designed by Santini, the author of the details was František Maxmilián Kaňka. The building that denies all the usual ideas about church architecture that has become a famous jewel of the World Cultural Heritage is the area of ​​the church of St John of Nepomuk at Zelená hora in Žďár nad Sázavou.

Santini's personal life is even less known than his professional activities. In 1705, he bought his own house in Prague and obtained the Lesser Town burgher status. He soon bought the neighboring house as well and combined the two. However, he was not allowed to carry on his own business in Prague because he was not a member of the Prague Masons' Guild. His only customers in Prague could be nobility or church institutions, who were not subject to the guild regulations. In 1707, Jan Blažej married Veronika Alžběta Schröderová, the daughter of the painter Krystián Schröder. He became the father of four children, but all three sons (Jan Norbert Lukáš, Josef Rudolf Felix Řehoř and František Ignác) died as children from tuberculosis. Only his daughter Anna Veronika, born fourth in order, survived. Santini's first marriage lasted thirteen years; his wife Veronika Alžběta died in 1720. Santini did not stay alone with his then seven-year-old daughter for long. His next wife was Antonie Ignatie Chřepická from Modliškovice. This South Bohemian noblewoman gave birth to Santini`s two further children, a daughter Johanna Ludmila and a son Johann Ignatius Roch, who was born in August 1723.

Santini's last will and testament was dated as of December 5, 1723. Two days later, the architect, who was only forty-six years old, died. As his final resting place, he did not choose a lavish building but a modest church of St John in Obora (in Prague's Lesser Town). But he was not granted with an undisturbed rest. The church was abolished in 1784 by the decrees of the Emperor Joseph II and closed two years later. In 1791, the church and parts of the cemetery fell into private hands. The church was rebuilt into a residential house, the crypt was turned into a cellar, the cemetery was transformed into a garden and only a cross and a memorial plaque on the former cemetery wall commemorate its existence today. The fate of Santini's remains is unknown.