Aeneas was born to Silvio, a soldier and member of the House of Piccolomini, and Vittoria Forteguerri, who had 18 children including several twins, though most died at a young age. He worked with his father in the fields for some years and at age 18 left to study at the universities of Siena and Florence. He settled in the former city as a teacher, but in 1431 accepted the post of secretary to Domenico Capranica, bishop of Fermo, then on his way to the Council of Basel (1431–39). Capranica was protesting against the new Pope Eugene IV's refusal of a cardinalate for him, which had been designated by Pope Martin V. Arriving at Basel after enduring a stormy voyage to Genoa and then a trip across the Alps, he successively served Capranica, who ran short of money, and then other masters.
In 1435 he was sent by Cardinal Albergati, Eugenius IV's legate at the council, on a secret mission to Scotland, the object of which is variously related even by himself. He visited England as well as Scotland, underwent many perils and vicissitudes in both countries, and left an account of each. The journey to Scotland proved so tempestuous that Piccolomini swore that he would walk barefoot to the nearest shrine of Our Lady from their landing port. This proved to be Dunbar; the nearest shrine was 10 miles distant at Whitekirk. The journey through the ice and snow left Aeneas afflicted with pain in his legs for the rest of his life. Only when he arrived at Newcastle, did he feel that he had returned to "a civilised part of the world and the inhabitable face of the Earth", Scotland and the far north of England being "wild, bare and never visited by the sun in winter". In Scotland, he fathered a child but it died.
Upon his return to Basel, Aeneas sided actively with the council in its conflict with the Pope, and, although still a layman, eventually obtained a share in the direction of its affairs. He supported the creation of the Antipope Felix V (Amadeus, Duke of Savoy) and participated in his coronation. Aeneas then was sent to Strasbourg where he fathered a child with a Breton woman called Elizabeth. The baby died 14 months later. He then withdrew to the court of Holy Roman Emperor Emperor Frederick III in Vienna. He had been crowned imperial poet laureate in 1442, and he obtained the patronage of the emperor's chancellor, Kaspar Schlick. Some identify the love adventure at Siena that Aeneas related in his romance The Tale of the Two Lovers with an escapade of the chancellor.
Aeneas' character had hitherto been that of an easy and democratic-minded man of the world with no pretense to strictness in morals or consistency in politics. He now began to be more regular in the former respect, and in the latter adopted a decided line by making his peace between the Empire and Rome.censures and returned to Germany under an engagement to assist the Pope. This he did most effectually by the diplomatic dexterity with which he smoothed away differences between the papal court of Rome and the German imperial electors. He played a leading role in concluding a compromise in 1447 by which the dying Pope Eugene accepted the reconciliation tendered by the German princes. As a result, the council and the antipope were left without support. He had already taken orders, and one of the first acts of Pope Eugene's successor, Pope Nicholas V (1447–1455), was to make him Bishop of Trieste. He later served as Bishop of Siena.
Being sent on a mission to Rome in 1445, with the ostensible object of inducing Pope Eugene to convoke a new council, he was absolved from ecclesiastical
In 1450 Aeneas was sent as ambassador by the Emperor Frederick III to negotiate his marriage with Princess Eleonore of Portugal. In 1451 he undertook a mission to Bohemia and concluded a satisfactory arrangement with the Hussite leader George of Poděbrady. In 1452 he accompanied Frederick III to Rome, where Frederick wedded Eleanor and was crowned emperor by the pope. In August 1455 Aeneas again arrived in Rome on an embassy to proffer the obedience of Germany to the new pope, Calixtus III. He brought strong recommendations from emperor Frederick and Ladislaus V of Hungary (also King of Bohemia) for his nomination to the cardinalate, but delays arose from the Pope's resolution to promote his own nephews first, and he did not attain the object of his ambition until December of the following year. He did acquire temporarily the bishopric of Warmia (Ermeland).