In 1860, aged 20, Cleve became assistant professor of mineralogy at the University of Uppsala, and was appointed assistant professor of chemistry in 1868. He also taught at the Royal Institute of Technology between 1870 and 1874, and eventually became professor of general and agricultural chemistry at the University of Uppsala. He was the chair of chemistry at the University of Uppsala starting in 1874. He was also the president of the Nobel Committee for Chemistry.
Cleves first work was Några ammoniakaliska chromföreningar (Some compounds of ammonia and chromium', 1861). He also wrote several more papers on complex compounds, including the compounds of platinum. Additionally, Cleve synthesized several hundred complex platinum compounds.
Cleve visited a number of laboratories in England, France, Italy, and Switzerland in the 1860s. While in Paris, he visited the laboratory of Charles-Adolphe Wurtz and also made a number of friends there.
Cleve worked on the synthesis of complex chemical compounds until 1872. He theorized in 1874 that the element didymium consisted of two elements. This theory was proven right with the discovery of praseodymium and neodymium in 1885 by Carl Auer von Welsbach. In 1879, Cleve proved that the newly discovered element scandium was an element predicted by Dmitri Mendeleev to be "eka-boron". He isolated a quantity of scandium in this same year and determined its atomic weight. He discovered the element holmium in 1879 by examining a sample of erbium oxide. While removing impurities from a sample of erbium oxide, Cleve discovered a brown substance and a green substance, and the brown substance was holmium oxide (the green substance was thulium oxide). However, this sample may have been impure. He separated thulium from an erbium oxide sample in 1879. Additionally, Cleve and Abraham Langlet discovered helium in the mineral cleveite in 1895.
Cleve discovered six forms of dichloronaphthalene and discovered  aminonaphthalenesulfonic acids, which are sometimes named after him. He prepared a number of nitrosulfonic acids as well. In 1883, Cleve was the first person to describe the plankton species Nitzschia seriata. In 1890, Cleve began to mainly focus on the  field of biology, mainly studying freshwater algae, diatoms, and plankton. Cleve participated in a Swedish expedition to Spitsbergen in 1898. While on this mission, he discovered a number of species of spumellarians, nassellarians, and phaeodarians.
Cleve, in collaboration with 
Otto Höglund 
prepared numerous previously-undiscovered salts of yttrium and erbium. The two also did work on the chemistry of the chemical elements thorium and lanthanum. By 1874, Cleve discovered that thorium was a quadrivalent element and also determined lanthanum to be trivalent. These findings were initially doubted by the scientific community.
Cleve was the first observer of isomerism in platinumamine derivatives.
Additionally, Cleve created a method of dating glacial and post-glacial deposits in the fossil record.
Cleves PhD dissertation was "Mineral-analytiska under-sökningar". He wrote a paper on samarium in 1879 and The Seasonal Distribution of Atlantic Plankton Organisms in 1900. In 1883, he published Kemiskt Handlexicon, which translates to Chemical Handbook'. Notable students of Cleve include Ellen Fries (the first Swedish woman to earn a PhD) and Svante Arrhenius (a winner of the Nobel Prize).
Cleve also studied hydrography and geology.