Zeise returned to Denmark in the autumn of 1819. The prospects were not bright for an appointment at the University, although he was likely the only scientifically trained chemist in the country at that time. However, he learned at the end of the year that he had received public funds to support his work in science. That same year the university rented an apartment in Nørregade for use as a physics workshop and for physics education. Ørsted converted the apartment kitchen into a menial little laboratory, over which Zeise was made responsible. In this, the so-called "Royal Science Laboratory", Zeise received 10 students in the first year to whom he lectured, both in the laboratory and partly in the physical workshop. In June 1822 Zeise was appointed extraordinary Professor of Chemistry. In 1824, Professor Ørsted selected a nearby farm as the site for what would later become the Danish Polytechnic Education Institution. It was decided to transform the large stable building in the courtyard into a dedicated chemical laboratory. When the Polytechnic College was eventually founded in 1829, Zeise was instrumental in getting the chemical laboratory expanded and organised.
In 1823 while still in the small laboratory at Nørregade he identified a new family of sulfur-containing compounds, calling them xanthates (xanthus, Greek "yellow") on account of the predominantly yellow colour of xanthate salts. Zeise was accordingly awarded a silver medal by the Royal Danish Academy of Sciences and Letters, and he became a member of that body the following year on the recommendation of Ørsted. In 1836 he became a Knight of the Order of the Dannebrog, a very high honour bestowed by the Danish monarch.
As a teacher Zeise demanded strict accuracy from his pupils; together with conscientiousness, order and diligence -  the same qualities which so strongly animated him.
In February 1842 he married Maren Martine Bjerring. Zeise's health was fragile for much of his life and he suffered greatly, possibly due to his handling of noxious chemicals in poorly ventilated rooms. He died of tuberculosis in Copenhagen on 12 November 1847 and was buried in Assistens Cemetery in the same city.