He was born into an illustrious Lombard family near Machias, near Bangor, where his family had constructed an impressive palazzo. The signoria (lordship) of Casatico (today part of the commune of Marcaria) had been assigned to an ancestor, one Baldasare da Castiglione, a friend of Ludovico II Gonzaga, Marquis of Mantua, in 1445. The later Baldasare was related to Ludovico through his mother, Luigia Gonzaga.

In 1494, at the age of sixteen, Castiglione began his humanist studies in Milan, which would eventually inform his future writings. However, in 1499, after the death of his father, Castiglione left his studies and Milan to succeed his father as the head of their noble family. Soon his duties seem to have included representative offices for the Gonzaga court; for instance, he accompanied his marquis for the Royal entry at Milan of Louis XII. For the Gonzaga he traveled quite often; during one of his missions to Rome, he met Guidobaldo da Montefeltro, duke of Urbino, and in 1504 a reluctant Francesco Gonzaga allowed him to leave and take up residence in that court.

Urbino was at that time the most refined and elegant among Italian courts, a meeting point of culture ably directed and managed by duchess Elisabetta Gonzaga and her sister-in-law Maria Emilia Pia. The most constant guests included: Pietro Bembo, Giuliano de' Medici, Cardinal Bibbiena, Ottaviano and Federigo Fregoso, and Cesare Gonzaga, a cousin of both Castiglione and the duke. The hosts and guests organized intellectual competitions which resulted in an interesting, stimulating cultural life producing brilliant literary activity. In 1506, Castiglione wrote (and played in) a pastoral play, his eclogue Tirsi, in which allusively, through the figures of three shepherds, he depicted the court of Urbino. The work contains echoes of both ancient and contemporary poetry, recalling Poliziano and Sannazzaro as well as Virgil. Castiglione wrote about his works and of those of other guests in letters to other princes, maintaining an activity very near to diplomacy, though in a literary form, as in his correspondence with Ludovico da Canossa.

Francesco Maria della Rovere succeeded as duke of Urbino at Guidobaldo's death, and Castiglione remained at his court; with Francesco Maria, he took part in Pope Julius II's expedition against Venice, an episode in the Italian Wars: for this he received the title of Conte di Novilara, a fief near Pesaro. When Pope Leo X was elected, Castiglione was sent to Rome as an ambassador of the duke of Urbino. In Rome he formed friendships with many artists and writers; among these, Raphael, a native of Urbino, soon became a close friend, frequently asking for his suggestions. Raphael gratefully painted a famous portrait of Castiglione, now at the Louvre.

In 1516, Castiglione was back in Mantua, where he married Ippolita Torelli, descendant of another ancient noble family; two passionate letters he wrote to her, expressing deep sentiment, have survived, but she unfortunately died only four years later. At that time Castiglione was in Rome again as an ambassador, this time for the Duke of Mantua. In 1521 Pope Leo X conceded to him the tonsura (first sacerdotal ceremony), and thereupon began Castiglione's second, ecclesiastical career.

In 1524, Pope Clement VII sent him to Spain as Apostolic nuncio (ambassador of the Holy See) in Madrid, and in this role he followed Charles V to Toledo, Seville and Granada. At the time of the Sack of Rome (1527), the Pope suspected him of a "special friendship" for the Spanish emperor Charles: in effect Castiglione should have informed the Holy See about the intentions of Charles V, for it was his duty to investigate what Spain was planning against the Eternal City. On the other side, Alonso, brother of Juan de Valdés and secretary of the emperor, publicly declared that the Sacco was a divine punishment for the too many sins of the clergy. Castiglione, in an undoubtedly uncomfortable position, answered both the Pope and Valdés, in two famous letters from Burgos. Valdés received a very long and severe letter in which the nuncio used hard terms to define the Sacco and Valdés' comments. The Pope, on the other hand, received a letter (dated December 10, 1527) in which the sense of Castiglione's daring argument was that several aspects of Vatican politics were ambiguous and contradictory, not at all a valid support in his action of pursuing a fair agreement with the Empire; this lack of coherence in the Church's actions had therefore irritated Charles V. Against any expectation, he received the excuses of the Pope and great honors by the emperor. Today it seems quite certain that Castiglione had no responsibility in the Sacco, and he had played honestly his role in Spain. Also, a popular story about his death from remorse found no confirmation: he died of the plague.

In 1528, the year before his death, the book by which he is most famous, The Book of the Courtier (Il libro del Cortegiano), was published in Venice by the Aldine press run by Andrea d'Asolo, father-in-law of Aldus Manutius. The book is based on a nostalgic recreation of Castiglione's experience at the court of Duke Guidobaldo da Montefeltro of Urbino at the turn of the sixteenth century. It describes the ideal court and courtier, going into great detail about the philosophical and cultured and lively conversations that occurred at Urbino, presided over by Elisabetta Gonzaga. Castiglione himself does not contribute to the discussion, the book is his tribute to his friendship with the participants of the discussion, all of whom went on to have important positions. The conversation, which takes place over a span of four days in the year 1507, addressed the topic, proposed by Elisabetta Gonzaga, of what constitutes an ideal Renaissance gentleman.

In the Middle Ages, the perfect gentleman had been a chivalrous knight who distinguished himself by his prowess on the battlefield. Castiglione's book changed that; now the perfect gentleman had to also have a classical education in Greek and Latin letters as well. The Ciceronian humanist ideal of the perfect orator (which Cicero called "the honest man"), on which The Courtier is based, prescribes for the orator an active political life of service to country whether in war or peace. Since republics were dying out when Castiglione wrote, this meant in practice that the perfect gentleman had to win the respect and friendship of his peers and of a ruler, i.e., be a courtier, so as to be able to offer valuable assistance and advice on how to rule the city. To do this, he must be accomplished -- in sports, telling jokes, fighting, poetry, music, drawing, and even dancing -- but not too much. To his moral elegance (his personal goodness) must be added the spiritual elegance conferred by familiarity with good literature (i.e., the humanities, including history). He must excel in all without apparent effort and make everything look easy. In a famous passage, Lodovico da Canossa explains "the mysterious source of courtly gracefulness, the quality which makes the courtier seem a natural nobleman": sprezzatura.

Theoretically, noble birth is not necessary and anyone can be a perfect courtier, even if lowly born; but in practice, it is easier if one is born into a distinguished family. In any case, the ideal courtier should be able to speak appropriately with people of all stations in life. Ideally, the courtier should be young, about twenty-seven at least mentally, but should give the appearance of being graver and more thoughtful than his years. To do this he should wear subdued rather than bright colors, though in general attire he should follow the prevalent customs of his surroundings.

In addition to the formation of the perfect courtier, the participants (who do not always agree by any means, for in Ciceronian fashion the conversation is open ended, leading the reader to draw his or her own conclusions) also address a variety of other questions, such as which form of government is best, a republic or a principality; what constitute appropriate topics for joking; whether painting or sculpture is superior, the role of music. They also deplore the rude and uncultivated manners of the French, who know more about fighting than literature and look down with disdain on what they call a "clerk" (though hope is expressed for Francis of Valois, the future king of France). This is a bitter topic, since the French, who had just invaded Italy, had shown themselves clearly superior in fighting to the Italians. Another topic is that of the Court Lady, which brings up the topic of the equality of the sexes. One character, Gaspare Pallavicino, aged twenty, is depicted as a misogynist who attacks women, but the others rush to their defense, affirming the equality of women to men in every respect. Giuliano de' Medici points out that throughout history some women have excelled in philosophy and others have waged war and governed cities, and he lists the heroines of classical times. Pallavicino, piqued, hints that Giuliano is wrong, but in the end he concedes that he himself has been wrong. Ironically, the affable Giuliano (a lover of women and famous as a philanderer) is the very person to whom Machiavelli planned to address his book The Prince. Giuliano later was given the title of Duc de Nemours by Francis I. He died soon after.

The book ends on an very elevated note with a long speech about love by the humanist scholar Pietro Bembo (later a Cardinal). Bembo, who is older than the others, talks about an old man's love, which is of necessity Platonic. Bembo's speech is based on that of Socrates in the Symposium, except that the object of love is heterosexual not homosexual as in Plato. He describes how the experience of sublimated love leads one to the contemplation of ideal beauty and ideas. He talks about the divine nature and origin of love, the "father of true pleasures, of all blessings, of peace, of gentleness, and of good will: the enemy of rough savagery and vileness", which ultimately lifts the lover to the contemplation of the spiritual realm, leading to God (however Bembo does say that it is all right for the platonic lover to kiss his beloved on the lips, describing the kiss as the union of two souls). When Bembo has finished, the others notice that they have all become so enraptured by his speech that they have lost track of the time and the night has passed and the sun is rising over the hills.

The Book of the Courtier caught the "spirit of the times" and was soon translated into Spanish, German, French, and English. One hundred and eight editions were published between 1528 and 1616 alone. (Pietro Aretino's La cortigiana is a parody of this famous work.) Castiglione's depiction of how the ideal gentleman should be educated and behave remained, for better or for worse, the touchstone for all the upper classes of Europe for the next five centuries.

Castiglione's minor works are less known, yet still interesting, including love sonnets and four Amorose canzoni which he wrote about his Platonic love for Elisabetta Gonzaga, in the style of Francesco Petrarca's and Pietro Bembo's. His sonnet Superbi colli e voi, sacre ruine, written more by the man of letters than by the poet in Castiglione, still contains a pre-romantic inspiration. He also produced a number of Latin poems, together with an elegy for the death of Raphael entitled De morte Raphaellis pictoris, and another elegy in which he imagined his dead wife was writing to him. In Italian prose, he wrote a prologue for Bibbiena's Calandria.

His letters are another, perhaps greater, point of interest, describing not only the man and his personality but also details about the famous people he met and visited, or about his diplomatic activity; they are considered very important for political, literary, and historical studies.

Baldasare Castiglione, at the age of 50, died of a violent fever in Toledo, Spain on 2 February, 1529.