Paolo dal Pozzo Toscanelli was born in Florence, the son of the physician Dominic Toscanelli. Educated in mathematics at the University of Padua, he left in 1424 with the title of a doctor of medicine.

Toscanelli is noted for his observations of comets and the painstaking calculation of their orbits. Among these was the comet of 1456; only named Halley's comet when Halley confirmed its return in 1768.

Thanks to his long life, his intelligence and his wide interests, Toscanelli was one of the central figures in the intellectual and cultural history of Renaissance Florence in its early years. His circle of friends included the architect of the Duomo, Filippo Brunelleschi, and the philosopher Marsilio Ficino; he knew Leon Battista Alberti, mathematician, writer and architect; and his closest friend was Cardinal Nicholas of Cusa, himself a wide - ranging intellect and early humanist, who dedicated two short mathematical works, both written in 1445, to Toscanelli, and made himself and Toscanelli the interlocutors in a dialogue entitled ‘On Squaring the Circle (De quadratura circuli) written in 1458.

Toscanelli along with Nicholas of Cusa (Cusanus) appears to have belonged to a network of Florentine and Roman intellectuals who searched for and studied Greek mathematical works, along with Filelfo, George of Trebizond, and the humanist Pope Nicholas V, in company with Toscanelli’s friends Alberti and Brunelleschi.

Around 1468 Toscanelli devised the gnomon still to be seen in the Cathedral of Santa Maria del Fiore in Florence: a bronze plate let into the dome high above the left transept, and a circular white marble slab let into the floor of the Cathedral, which records the summer solstice to a half - second, and which was then and subsequently used for centuries for other calculations such as the regular movement of the sun; effectively a Camera Obscura.

In 1439, the Greek philosopher Gemistos Plethon, attending the Council of Florence, acquainted Toscanelli with the extensive travels, writings and mapping of the 1st century BCE / CE Greek geographer Strabo, hitherto unknown in Italy. Nearly 35 years later, the Italian was to follow up this amplified knowledge.

In 1474 Toscanelli sent a letter and a map to his Portuguese correspondent Fernão Martins, priest at the Lisbon Cathedral, detailing a scheme for sailing westwards to reach the Spice Islands and Asia. Fernão Martins delivered his letter to the King Afonso V of Portugal, in his court of Lisbon. The original of this letter was lost, but its existence is known through Toscanelli himself, who later transcribed it along with the map and sent it to Christopher Columbus, who carried them with him during his first voyage to the new world. Toscanelli had miscalculated the size of the earth which resulted in Columbus never realizing he had found a new continent.

Toscanelli lived most of his life in Florence, with occasional excursions to Todi and Rome. He is said to have entered into correspondence with scholars around Europe, but his writings have yet to be thoroughly researched.

An uncorroborated story links Toscanelli's attendance at a Chinese delegation to the Pope in 1432, when many Chinese inventions were discussed, with a flood of drawings made around the same year by the artist - engineer Taccola (1382 - c.1453), which were later developed by Brunelleschi and Leonardo da Vinci. In a 1474 letter of Toscanelli to Columbus, the authenticity of which has been a matter of disagreement among scholars, Toscanelli mentions the visit of men from Cathay (China) during the reign of Pope Eugenius IV (1431 - 1447):

"Also in the time of Eugenius one of them [of Cathay] came to Eugenius, who affirmed their great kindness towards Christians, and I had a long conversation with him on many subjects, about the magnitude of their rivers in length and breath, and on the multitude of cities on the banks of rivers. He said that on one river there were near 200 cities with marble bridges great in length and breadth, and everywhere adorned with columns. This country is worth seeking by the Latins, not only because great wealth may be obtained from it, gold and silver, all sorts of gems, and spices, which never reach us; but also on account of its learned me, philosophers, and expert astrologers, and by what skill and art so powerful and magnificent a province is governed, as well as how their wars are conducted."

— Extract of the First Letter of Paolo Toscanelli to Columbus.

It has been suggested that the man in question may have been Niccolo da Conti, who was returning from the east and is known to have met with Pope Eugenius in 1444. In a second letter, Toscanelli further describes these men as extremely learned and willing to share their knowledge:

"The said voyage is not only possible, but it is true, and certain to be honourable and to yield incalculable profit, and very great fame among all Christians. But you cannot know this perfectly save through experience and practice, as I have had in the form of the most copious and good and true information from distinguished men of great learning who have come from the said parts, here in the court of Rome, and from others being merchants who have had business for a long time in those parts, men of high authority."

— Extract of the First Letter of Paolo Toscanelli to Columbus.