An exact and conscientious worker, Klaproth did much to improve and systematise the processes of analytical chemistry and mineralogy. His appreciation of the value of quantitative methods led him to become one of the earliest adherents of the Lavoisierian doctrines outside France.
Klaproth was the first to discover uranium, identifying it first in torbernite but doing the majority of his research on it with the mineral pitchblende. 
On 24 September 1789 he announced his discovery to the Royal Prussian Academy of sciences in Berlin.
He also discovered zirconium in 1789, separating it in the form of its earth zirconia, oxide ZrO2.
Klaproth analyzed a brightly-colored form of the mineral called "hyacinth" from Ceylon. He gave the new element the name zirconium based on its Persian name "zargun", gold-colored.
Klaproth characterised uranium and zirconium as distinct elements, though he did not obtain any of them in the pure metallic state.
Klaproth independently discovered  cerium (1803), a rare earth element, around the same time as Jöns Jacob Berzelius and Wilhelm Hisinger, in the winter of 1803.
William Gregor of Cornwall was the first to identify the element titanium in 1791, correctly concluding that he had found a new element in the ore ilmenite from the Menachan valley. He proposed the name "menachanite", but his discovery attracted little attention.  
Klaproth verified the presence of an oxide of an unknown element in the ore rutile from Hungary in 1795. Klaproth suggested the name "titanium".  It was later determined that menachanite and titanium were the same element, from two different minerals, and Klaproth's name was adopted.
Klaproth clarified the composition of numerous substances until then imperfectly known, including compounds of then newly recognised elements tellurium, strontium and chromium.
Chromium was discovered in 1797 by Louis Nicolas Vauquelin and independently discovered in 1798 by Klaproth and by Tobias Lowitz, in a mineral from the Ural mountains. Klaproth confirmed chromium's independent status as an element.
The existence of tellurium was first suggested in 1783 by Franz-Joseph Mueller von Reichenstein, an Austrian mining engineer who was examining Transylvanian gold samples.  Tellurium was also discovered independently by Hungarian Pál Kitaibel in 1789. Mueller sent some of his mineral to Klaproth in 1796. Klaproth isolated the new substance and confirmed the identification of the new element tellurium in 1798. He credited Mueller as its discoverer, and suggested that the heavy metal be named "tellus", Latin for earth.
In 1790 Adair Crawford and William Cruickshank determined that the mineral strontianite, found near Strontian in Scotland, was different from barium-based minerals. 
Klaproth was one of several scientists involved in the characterization of strontium compounds and minerals.  
Klaproth, Thomas Charles Hope, and 
Richard Kirwan independently studied and reported on the properties of strontianite, the preparation of compounds of strontium, and their differentiation from those of barium. In September 1793, Klaproth published on the separation of strontium from barium, and in 1794 on the preparation of strontium oxide and strontium hydroxide. 
In 1808, Humphry Davy became the first to successfully isolate the pure element.
Louis Nicolas Vauquelin reported the existence of a new element common to emerald and beryl in 1798, and suggested that it be named "glucine". Klaproth confirmed the presence of a new element, and became involved in a lengthy and ongoing debate over its name by suggesting "beryllia". The element was first isolated in 1828, independently by Friedrich Wöhler and Antoine Bussy. Only in 1949 did IUPAC rule exclusively in favor of the name beryllium.
Klaproth published extensively, collecting over 200 papers by himself in Beiträge zur chemischen Kenntnis der Mineralkörper (5 vols., 1795–1810) and Chemische Abhandlungen gemischten Inhalts (1815). He also published a Chemisches Wörterbuch (1807–1810), and edited a revised edition of F. A. C. Grens Handbuch der Chemie' (1806).
Klaproth became a foreign member of the Royal Society of London in 1795, and a foreign member of the Royal Swedish Academy of Sciences in 1804.
He also belonged to the Institut de France.
The crater Klaproth on the Moon is named after him.
In 1823, botanist Carl Sigismund Kunth published a genus of flowering plants (belonging to the family Loasaceae), from Central America as Klaprothia in his honour.
His son Julius was a famous orientalist.