There has been over a century of speculation that Botticelli himself may actually have been homosexual. Many Writers observed homo-eroticism in his portraits. The American art Historian, Bernard Berenson, for Example, detecting what he believed to be latent homosexuality. In 1938, Jacques Mesnil discovered a summary of a charge in the Florentine Archives for November 16, 1502, which read simply "Botticelli keeps a boy", an accusation of sodomy (homosexuality). No prosecution was brought. The Painter would then have been about fifty-eight. Mesnil dismissed it as a customary slander by which partisans and adversaries of Savonarola abused each other. Opinion remains divided on whether this is evidence of bisexuality or homosexuality. Many have backed Mesnil,; the art Historian, Scott Nethersole, has suggested that a quarter of men in Florentine were the subject of similar accusations, which "seems to have been a standard way of getting at people". but others have cautioned against hasty dismissal of the charge. Mesnil nevertheless concluded "woman was not the only object of his love".

Botticelli continued to pay his dues to the Compagnia di San Luca (a confraternity rather than the artist's guild) until at least October 1505; the tentative date ranges assigned to his late paintings run no further than this. By then he was aged sixty or more, in this period definitely into old age. Vasari, who lived in Florence from around 1527, says that Botticelli died "ill and decrepit, at the age of seventy-eight", after a period when he was "unable to stand upright and moving around with the help of crutches". He died in May 1510, but is now thought to have been something under seventy at the time. He was buried with his family outside the Ognissanti Church in a spot the church has now built over. This had been his parish church since he was baptized there, and contained his Saint Augustine in His Study.

There are a few mentions of paintings and their location in sources from the decades after his death. Vasari's Life is relatively short and, especially in the first edition of 1550, rather disapproving. According to the Ettlingers "he is clearly ill at ease with Sandro and did not know how to fit him into his evolutionary scheme of the history of art running from Cimabue to Michelangelo". Nonetheless, this is the main source of information about his life, even though Vasari twice mixes him up with Francesco Botticini, another Florentine Painter of the day. Vasari saw Botticelli as a firm partisan of the anti-Medici faction influenced by Savonarola, while Vasari himself relied heavily on the patronage of the returned Medicis of his own day. Vasari also saw him as an Artist who had abandoned his talent in his last years, which offended his high idea of the artistic vocation. He devotes a good part of his text to rather alarming anecdotes of practical jokes by Botticelli.

In 1621 an picture-buying agent of Ferdinando Gonzaga, Duke of Mantua bought him a painting said to be a Botticelli out of historical interest "as from the hand of an Artist by whom Your Highness has nothing, and who was the master of Leonardo da Vinci". That mistake is perhaps understandable, as although Leonardo was only some six years younger than Botticelli, his style could seem to a Baroque judge to be a generation more advanced.

The English collector william Young Ottley bought Botticelli's The Mystical Nativity in Italy, bringing it to London in 1799. But when he tried to sell it in 1811, no buyer could be found. After Ottley's death, its next purchaser, william Fuller Maitland of Stansted, allowed it to be exhibited in a major art exhibition held in Manchester in 1857, the Art Treasures Exhibition, where among many other art works it was viewed by more than a million people. His only large painting with a mythological subject ever to be sold on the open market is the Venus and Mars, bought at Christie's by the National Gallery for a rather modest £1,050 in 1874.

The Birth of Venus was displayed in the Uffizi from 1815, but is little mentioned in travellers' accounts of the gallery over the next two decades. The Berlin gallery bought the Bardi Altarpiece in 1829, but the National Gallery, London only bought a Madonna (now regarded as by his workshop) in 1855.

Walter Pater created a literary picture of Botticelli, who was then taken up by the Aesthetic movement. The first monograph on the Artist was published in 1893, the same year as Aby Warburg's seminal dissertation on the mythologies; then, between 1900 and 1920 more books were written on Botticelli than on any other Painter. Herbert Horne's monograph in English from 1908 is still recognised as of exceptional quality and thoroughness, "one of the most stupendous achievements in Renaissance studies".

Ernst Steinmann (d. 1934) detected in the later Madonna's a "deepening of insight and expression in the rendering of Mary's physiognomy", which he attributed to Savonarola's influence (also pushing back the dating of some of these Madonnas. More recent scholars are reluctant to assign direct influence, though there is certainly a replacement of elegance and sweetness with forceful austerity in the last period.

The main belt asteroid 29361 Botticelli discovered on 9 February 1996, is named after him.

Botticelli appears as a character, sometimes a main one, in numerous fictional depictions of 15th-century Florence in various media. He will be portrayed by Sebastian de Souza in the second season of the TV series Medici: Masters of Florence.

Botticelli's Virgins are always beautiful, in the same idealized way as his mythological figures, and often richly dressed in contemporary style. Although Savonarola's main strictures were against secular art, he also complained of the paintings in Florentine churches that "You have made the Virgin appear dressed as a whore", which may have had an effect on Botticelli's style. They are often accompanied by equally beautiful angels, or an infant Saint John the Baptist (the patron saint of Florence). Some feature flowers, and none the detailed landscape backgrounds that other artists were developing. Many exist in several versions of varying quality, often with the elements other than the Virgin and Child different. Many of these were produced by Botticelli or, especially, his workshop, and others apparently by unconnected artists. When interest in Botticelli revived in the 19th century, it was initially largely in his Madonnas, which then began to be forged on a considerable scale.