After the death of J. F. Meckel (1781–1833) he edited the Archiv für Anatomie und Physiologie.

When he was 18 though, his love for natural science became dominant, and he turned to Medicine, entering the University of Bonn in 1819. There he received his M.D.. He then studied at Berlin. There, under the influence of Hegel and Rudolphi, he was induced to reject all systems of physiology which were not founded upon a strict observation of nature.

He became Privatdozent of physiology and comparative anatomy at Bonn in 1824, extraordinary professor of physiology in 1826, and ordinary professor in 1830. In 1833 he went to the Humboldt University of Berlin, where he filled the chair of anatomy and physiology until his death.

Müller made contributions in numerous domains of physiology, in particular increasing understanding of the voice, speech and hearing, as well as the chemical and physical properties of lymph, chyle and blood. His first important works, Zur vergleichenden Physiologie des Gesichtsinns (“On the comparative physiology of sight,” Leipzig, 1826) and Über die phantastischen Gesichtserscheinungen (“On visual hallucination,” Coblenz, 1826), are of a subjective philosophical tendency. The first work concerns the most important facts as to human and animal sight, the second sounds depths of difficult psychological problems. He soon became the leader in the science of the morphological treatment of zoology as well as of experimental physiology. To his research (1830) is due the settlement of the theory of reflex action.

In the century preceding Müller's work, many contributions to physiological science had been made. Müller gave order to these facts, developed general principles and showed Physiologists how recent discoveries in physics and chemistry could be applied to their work. The appearance of his magnum opus, Handbuch der Physiologie des Menschen, between 1833 and 1840 (translated into English as “Elements of Physiology” by william Baly, and published in London 1837–1843) marked the beginning of a new period in the study of physiology. In it, for the first time, the results of human and comparative anatomy, as well as of chemistry and other departments of physical science, and tools like the microscope, were brought to bear on the investigation of physiological problems.

Müller mentored such distinguished Scientists and Physiologists as Hermann von Helmholtz, Emil du Bois-Reymond, Theodor Schwann, Friedrich Gustav Jakob Henle, Carl Ludwig and Ernst Haeckel. In 1834, he was elected a foreign member of the Royal Swedish Academy of Sciences.

Edward Forbes F.R.S. in his A History of British Starfishes, and Other Animals of the Class Echinodermata (1841) in his preface refers to Muller as the "one of the greatest living Physiologists, Muller of Berlin".

In addition to his Handbuch der Physiologie (translated by Baly in 1843: Elements of Physiology), his publications include:

Müller died in Berlin in 1858. In 1899, a bronze statue by Joseph Uphues was erected in his memory at Koblenz.

The book became the leading textbook in physiology for much of the nineteenth century. It manifests Müller’s interests in vitalism, philosophy and scientific rigor. He discusses the difference between inorganic and organic matter. He considers in detail various physiological systems of a wide variety of animals, but attributes the indivisible whole of an organism to the presence of a soul. He also proposes that living organisms possess a life-energy for which physical laws can never fully account.