During his puberty at the School of Jurisprudence, Tchaikovsky discovered his romantic attraction to other boys. As he matured to manhood he continued to engage in affairs with younger men. As a young man he was infatuated with a (female) soprano, but she married another man. One of his conservatory students, Antonina Milyukova, began writing him passionate letters around the time that he had made up his mind to "marry whoever will have me." He did not even remember her from his classes, but her letters were very persistent, and he hastily married her on July 18, 1877. Within days, while still on their honeymoon, he deeply regretted his decision. Two weeks after the wedding the composer attempted suicide by wading in a cold river. He later fled to Saint Petersburg a nervous wreck, and was separated from his wife after only six weeks. The couple never saw each other again. Antonina Milyukova died in a mental institution 24 years later. They remained legally married until his death.

The composer's homosexuality has long been generally accepted, as well as its importance to his music. His relationships have been documented by historians such as Rictor Norton, Alexander Poznansky and others.

A far more influential woman in Tchaikovsky's life was a wealthy widow, Nadezhda von Meck, with whom he exchanged 1,200 letters between 1877 and 1890. At her insistence they never met; they did encounter each other on two occasions, purely by chance, but did not converse. As well as financial support in the amount of 6,000 rubles a year, she expressed interest in his musical career and admiration for his music. However, after 14 years she ended the relationship unexpectedly, claiming bankruptcy. It was during this period that Tchaikovsky achieved success throughout Europe and (by his own account), in 1891, even greater accolades in the United States. In fact, he was the conductor, on May 5th, 1891, at the official opening night of Carnegie Hall.

Meck's claim of financial ruin is disregarded by some who believe that she ended her patronage of Tchaikovsky because she supposedly discovered the composer's homosexuality. It is possible she was planning to marry off one of her daughters to Tchaikovsky, as she also supposedly tried to marry one of them to Claude Debussy, who had lived in Russia for a time as music teacher to her family. Also, one of her sons, Nikolay, was married to Tchaikovsky's niece Anna Davydova.

Just nine days after the first performance of his Sixth Symphony, Pathétique, in 1893, in Saint Petersburg, Tchaikovsky died, most historians believe, of cholera. Some musicologists (Milton Cross, David Ewen) believe his Sixth Symphony was his own Requiem, and he knew it. In the development section of the first movement of that symphony, the rapidly progressing evolution of the transformed first theme suddenly "shifts into neutral" in the strings, and a rather quiet, harmonized chorale emerges in the trombones. The trombone theme bears absolutely no relation to the music that preceded it, and none to the music which follows it. It is a "non sequitur", an anomaly — except that it is from the Russian Orthodox Mass for the Dead, and is sung to the words: "And may his soul rest with the souls of all the saints." Tchaikovsky was interred in Tikhvin Cemetery at the Alexander Nevsky Monastery in Saint Petersburg.

His life, somewhat embroidered, is the subject of Ken Russell's motion picture The Music Lovers. His last name derives from the word chaika (чайка), meaning seagull in a number of Slavic languages. In an early letter to Nadezhda von Meck, Tchaikovsky wrote that his name was Russian and his ancestors were "probably Russian."