Mendeleev was born in Verhnie Aremzyani village, near Tobolsk, to Ivan Pavlovich Mendeleev and Maria Dmitrievna Mendeleeva (née Kornilieva). His grandfather was Pavel Maximovich Sokolov, a priest of Russian Orthodox Church from the Tver region. Ivan, along with his brothers and sisters, obtained new family names while attending theological seminary. At the age of 13, after the passing of his father and the destruction of his mother's factory by fire, Mendeleev attended the Gymnasium in Tobolsk.

In 1849, the now poor Mendeleev family relocated to Saint Petersburg, where he entered the Main Pedagogical Institute in 1850. After graduation, tuberculosis caused him to move to the Crimean Peninsula on the northern coast of the Black Sea in 1855. While there he became a science master of the Simferopol gymnasium №1. He returned with fully restored health to Saint Petersburg in 1857.

Between 1859 and 1861, he worked on the capillarity of liquids and the workings of the spectroscope in Heidelberg. On 4 April 1862 he had got engaged to Feozva Nikitichna Leshcheva, and they married on 27 April 1862 at Nikolaev Engineering College's church in Saint Petersburg. Mendeleev became Professor of Chemistry at the Saint Petersburg Technological Institute and Saint Petersburg State University in 1863. In 1865 he became Doctor of Science for his dissertation "On the Combinations of Water with Alcohol". He achieved tenure in 1867, and by 1871 had transformed Saint Petersburg into an internationally recognized center for chemistry research. In 1876, he became obsessed with Anna Ivanova Popova and began courting her; in 1881 he proposed to her and threatened suicide if she refused. His divorce from Leshcheva was finalized one month after he had married Popova in early 1882. Even after the divorce, Mendeleev was technically a bigamist; the Russian Orthodox Church required at least 7 years before lawful re-marriage. His divorce and the surrounding controversy contributed to his failure to be admitted to the Russian Academy of Sciences. Though Mendeleev was widely honored by scientific organizations all over Europe, including the Copley Medal from the Royal Society of London, he resigned from Saint Petersburg University on 17 August 1890.

In 1893, he was appointed Director of the Bureau of Weights and Measures. It was in this role that he was directed to formulate new state standards for the production of vodka. As a result of his work, in 1894 new standards for vodka were introduced into Russian law and all vodka had to be produced at 40% alcohol by volume. Mendeleev also investigated the composition of oil fields, and helped to found the first oil refinery in Russia.

In 1905, Mendeleev was elected a member of the Royal Swedish Academy of Sciences. The following year Nobel Committee for Chemistry recommended to the Swedish Academy to award the Nobel Prize in Chemistry for 1906 to Mendeleev for his discovery of the periodic system. The Chemistry Section of the Swedish Academy supported this recommendation. The Academy was then supposed to approve the Committee choice as it has done in almost every case. Unexpectedly, at the full meeting of the Academy, a dissenting member of the Nobel Committee, Peter Klason, proposed the candidacy of Henri Moissan whom he favored. Svante Arrhenius, although not a member of the Nobel Committee for Chemistry, had a great deal of influence in the Academy and also pressed for the rejection of Mendeleev, arguing that the periodic system was too old to acknowledge its discovery in 1906. According to the contemporaries, Arrhenius was motivated by the grudge he held against Mendeleev for his critique of Arrhenius's dissociation theory. After heated arguments, the majority of the Academy voted for Moissan. The attempts to nominate Mendeleev in 1907 were again frustrated by the absolute opposition of Arrhenius.

In 1907, Mendeleev died at the age of 72 in Saint Petersburg from influenza. The crater Mendeleev on the Moon, as well as element number 101,  the radioactive mendelevium, are named after him.