At just 18 years of age, Vaucanson was given his own workshop in Lyon, and a grant from a nobleman to construct a set of machines. In that same year of 1727, there was a visit from one of the governing heads of Les Minimes. Vaucanson decided to make some androids. The automatons would serve dinner and clear the tables for the visiting politicians. However one government official declared that he thought Vaucanson's tendencies "profane", and ordered that his workshop be destroyed.

In 1737, Vaucanson built The Flute Player, a life-size figure of a shepherd that played the tabor and the pipe and had a repertoire of twelve songs. The figure's fingers were not pliable enough to play the flute correctly, so Vaucanson had to glove the creation in skin. The following year, in early 1738, he presented his creation to the Académie des Sciences. At the time, mechanical creatures were somewhat a fad in Europe, but most could be classified as toys, and de Vaucanson's creations were recognized as being revolutionary in their mechanical life like sophistication.

Later that year, he created two additional automatons, The Tambourine Player and The Digesting Duck, which is considered his masterpiece. The duck had over 400 moving parts, and could flap its wings, drink water, digest grain, and defecate. Although Vaucanson's duck supposedly demonstrated digestion accurately, his duck actually contained a hidden compartment of "digested food", so that what the duck defecated was not the same as what it ate. Although such "frauds" were sometimes controversial, they were common enough because such scientific demonstrations needed to entertain the wealthy and powerful to attract their patronage. Vaucanson is credited as having invented the world's first flexible rubber tube while in the process of building the duck's intestines. Despite the revolutionary nature of his automatons, he is said to have tired quickly of his creations and sold them in 1743.

His inventions brought him to the attention of Frederick II of Prussia, who sought to bring him to his court. Vaucanson refused, however, wishing to serve his own country.

In 1741 he was appointed by Cardinal Fleury, chief minister of Louis XV, as inspector of the manufacture of silk in France. He was charged with undertaking reforms of the silk manufacturing process. At the time, the French weaving industry had fallen behind that of England and Scotland. Vaucanson promoted wide ranging changes for automation of the weaving process. In 1745, he created the world's first completely automated loom, drawing on the work of Basile Bouchon and Jean Falcon. Vaucanson was trying to automate the French textile industry with punch cards - a technology that, as refined by Joseph-Marie Jacquard more than a half century later, would revolutionize weaving and, in the twentieth century, would be used to input data into computers and store information in binary form. His proposals were not well received by weavers, however, who pelted him with stones in the street and many of the more revolutionary ones were largely ignored.

He invented several machine tools, such as the first fully documented, all metal slide rest lathe, around 1751 (Though Derry & Williams place this invention around 1768). It was described in the Encyclopédie.

In 1746, he was made a member of the Académie des Sciences.

Jacques de Vaucanson died in Paris in 1782. Vaucanson left a collection of his work as a bequest to Louis XVI. The collection would become the foundation of the Conservatoire des Arts et Métiers in Paris. His original automatons have all been lost. The flute player and the tambourine player were reportedly destroyed in the Revolution. His proposals for the automation of the weaving process, although ignored during his lifetime, were later perfected and implemented by Joseph Marie Jacquard, the creator of the Jacquard loom.

Lycee Vaucanson in Grenoble is named in his honor, and trains students for careers in engineering and technical fields.