- January 17 – Florentine explorer Giovanni da Verrazzano, on board La Dauphine in the service of Francis I of France, sets out from Madeira for the New World, to seek out a western sea route to the Pacific Ocean.
- March – Spanish conquistador Pedro de Alvarado destroys the K'iche' kingdom of Q'umarkaj, taking the capital, Quiché.
- March 1 (approximate date)– da Verrazzano's expedition makes landfall at Cape Fear.
- April 17 – Verrazzano's expedition makes the first European entry into New York Bay, and sights the island of Manhattan.  
- April 30 – Battle of the Sesia: Spanish forces under Charles de Lannoy defeat the French army in Italy, under William de Bonnivet. The French, now commanded by François de St. Pol, withdraw from the Italian Peninsula.
- June 8 – Battle of Acajutla: Spanish conquistador Pedro de Alvarado defeats a battalion of Pipiles, in the neighborhoods of present day Acajutla, El Salvador.
- February 10 – Albrecht Giese, German politician and diplomat (d. 1580)
- February 17 – Charles, Cardinal of Lorraine, French cardinal (d. 1574)
- May 28 – Selim II, Ottoman Sultan (d. 1574)
- June 12 – Achilles Statius, Portuguese humanist (d. 1581)
- June 24 – Johann Stössel, German theologian (d. 1576)
- August 14 – Elizabeth of Denmark, Duchess of Mecklenburg, Danish princess (d. 1586)
- August 23 – François Hotman, French Protestant lawyer and writer (d. 1590)
- September 7 – Thomas Erastus, Swiss theologian (d. 1583)
- September 11 – Pierre de Ronsard, French poet (d. 1585)
- October 4 – Francisco Vallés, Spanish physician (d. 1592)
- October 5 – Rani Durgavati, Queen of Gond (d. 1564)
- October 9 – Ottavio Farnese, Duke of Parma (d. 1586)
- October 16 – Nicolas, Duke of Mercœur, French Catholic bishop (d. 1577)
- November 12 – Diego de Landa, Bishop of the Yucatán (d. 1579)
- date unknown
- Jan Borukowski, royal secretary of Poland (d. 1584)
- Armand de Gontaut, baron de Biron, French soldier (d. 1592)
- Jean Pithou, French lawyer and author (d. 1602); and his twin brother, Nicolas Pithou, French lawyer and author (d. 1598)
- Thomas Tusser, English poet and farmer (d. 1580)
- Luís de Camões, Portuguese poet (d. 1580)
- Wenceslaus III Adam, Duke of Cieszyn (d. 1579)
- Catherine Carey, cousin of Elizabeth I of England (d. 1569)
- January 5 – Marko Marulić, Croatian poet (b. 1450)
- January 6 – Amalie of the Palatinate, duchess consort of Pomerania (b. 1490)
- February 10 – Catherine of Saxony, Archduchess of Austria (b. 1468)
- February 11 – Isabella of Aragon, Duchess of Milan, daughter of King Alfonso II of Naples (b. 1470)
- February 20 – Tecun Uman, K'iche' Mayan ruler (b. c. 1500)
- March 28
- April 14 – William Conyers, 1st Baron Conyers, English baron (b. 1468)
- April 30 – Pierre Terrail, seigneur de Bayard, French soldier (b. 1473)
- May 17 – Francesco Soderini, Italian Catholic cardinal (b. 1453)
- May 21 – Thomas Howard, 2nd Duke of Norfolk, English soldier and statesman (b. 1443)
- May 23 – Ismail I, Safavid Dynasty Shah of Persia (b. 1487)
- May 31 – Camilla Battista da Varano, Italian Roman Catholic nun and saint (b. 1458)
- June 12 – Diego Velázquez de Cuéllar, Spanish conquistador (b. 1465)
- July 9 – Sibylle of Brandenburg, Duchess of Jülich and Berg (b. 1467)
- July 20 – Claude of France, queen consort of Louis XII of France (b. 1499)
- August 4 – Helen of the Palatinate, Duchess of Pomerania (b. 1493)
- August 24 – William Scott, English Lord Warden of the Cinque Ports (b. 1459)
- September 18 – Charlotte of Valois, French princess (b. 1516)
- October 5 – Joachim Patinir, Flemish landscape painter (b. c. 1480)
- October 20 – Thomas Linacre, English humanist and physician (b. 1460)
- October 26 – Philip II, Count of Waldeck-Eisenberg (1486–1524) (b. 1453)
- December 24 – Vasco da Gama, Portuguese explorer (b. c. 1469)
- date unknown
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