In 1777, after two years of independent study, at the age of eighteen, Wolf went to the University of Göttingen. Legend has it that he chose to enroll in the department of philology", despite the fact that the university had none. His enrollment was nonetheless accepted as submitted. At the time Christian Gottlob Heyne was a member of the faculty. Heyne excluded Wolf him from his lectures, and criticized Wolf's views on Homer. Wolf was undeterred and pursued his studies through the university's library.
It was in Halle (1783–1807), with the support of ministers serving under Frederick the Great, that Wolf first laid down the principles of the field he would call "Philology". He defined philology as the study of human nature as exhibited in antiquity. Its method's include the examination of the history, writing, art and other examples of ancient cultures. It combines the study of history and language, through interpretation, in which history and linguistics coalesce into an organic whole. This was the ideal Wolf's philological seminarium at Halle.
During Wolf's time at Halle he published his commentary on the Leptines of Demosthenes (1789), which influenced his student Philipp August Böckh. He also published The Public Economy of Athens, and Prolegomena ad Homerum (1795). The publication of the latter led to accusations of plagiarism Heyne.
The Halle professorship ended after the French invasion of 1806. He relocated to Berlin, where he received assistance from Wilhelm von Humboldt. He died on the road to Marseille, and was buried there.