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|Ab urbe condita||2274|
|Balinese saka calendar||1442–1443|
|English Regnal year||12 Hen. 8 – 13 Hen. 8|
|Chinese calendar||庚辰年 (Metal Dragon)|
4217 or 4157
— to —
辛巳年 (Metal Snake)
4218 or 4158
|- Vikram Samvat||1577–1578|
|- Shaka Samvat||1442–1443|
|- Kali Yuga||4621–4622|
|Japanese calendar||Eishō 18 / Daiei 1|
|Minguo calendar||391 before ROC|
|Thai solar calendar||2063–2064|
1647 or 1266 or 494
— to —
1648 or 1267 or 495
|Wikimedia Commons has media related to 1521.|
- January 3 – Pope Leo X excommunicates Martin Luther, in the papal bull Decet Romanum Pontificem.
- January 22 – Charles V, Holy Roman Emperor, opens the Diet of Worms in Worms, Germany.
- January 27 – Suleiman the Magnificent suppresses a revolt by the ruler of Damascus.
- January 28 – The Diet of Worms begins, lasting until May 25.
- February 2 – The Nydala Abbey Bloodbath take place in Nydala Abbey, Sweden.
- March 6
- March 16 – Ferdinand Magellan reaches the Philippines.
- April 7
- April 16–18 – Martin Luther is examined before Emperor Charles V and the Diet of Worms, where he proclaims, "Here I stand", regarding his belief in the Bible alone, as the standard of Christian doctrine.
- April 24 – Revolt of the Comuneros – Battle of Villalar: Castilian royalists defeat the rebels and execute their three leaders.
- April 26 – Martin Luther leaves Worms and disappears for a year – he is rumored to be murdered, but is actually in hiding at the Wartburg castle.
- April 27 – Battle of Mactan: Ferdinand Magellan is killed in the Philippines.
- May – The Italian War of 1521–26 breaks out between Charles V, Holy Roman Emperor, and Francis I of France.
- May 17 – Edward Stafford, 3rd Duke of Buckingham, is executed for treason in London.
- May 20 – Battle of Pampeluna: The French defeat the Spanish.
- May 25 – The Diet of Worms ends when Charles V, Holy Roman Emperor issues the Edict of Worms, declaring Martin Luther an outlaw.
- May 27 – Jiajing Emperor ascends the throne of the Ming Dynasty.
- June 29 or 30 – The oldest surviving dateable document written primarily in the Romanian language: Neacșu's letter, written by a trader from Câmpulung, to Johannes Benkner, the mayor of Brașov, warning that the Ottoman Empire is preparing its troops to cross into Wallachia and Transylvania; the script used is Romanian Cyrillic.
- June 30 – Battle of Esquiroz: French forces under Henri d'Albret, exiled King of Navarre, are defeated by the Spanish, and forced to abandon their attempt to recover Henri's kingdom.
- July – Pfaffensturm: Students rebel against priests in Erfurt.
- August 8 – Fall of Tenochtitlan: Hernán Cortés and allied local indigenous peoples of the Americas defeat the Aztec forces of Cuauhtémoc, the last Tlatoani (Aztec Emperor), at Tenochtitlan in the Valley of Mexico.
- August 13 – Fall of Tenochtitlan: Cuauhtémoc surrenders to Cortés, thus incorporating the Aztec Empire into the Spanish Empire and ending the Late Postclassic period in Mesoamerica..
- August 23 – Christian II of Denmark is deposed as king of Sweden and Gustav Vasa is elected new Swedish regent.
- August 29 – Belgrade is captured by the Ottoman army of Suleiman the Magnificent.
- November 23 – Spanish–German–Papal forces under Prospero Colonna force French Marshal Odet de Lautrec to abandon Milan.
- December 27 – The Zwickau prophets arrive in Wittenberg, disturbing the peace and preaching the Apocalypse.
- March 21 – Maurice, Elector of Saxony (d. 1553)
- April 5 – Francesco Laparelli, Italian architect (d. 1570)
- April 14 – Johann Marbach, German theologian (d. 1581)
- April 18 – François de Coligny d'Andelot, French general (d. 1569)
- May 8 – Petrus Canisius, Dutch Jesuit (d. 1597)
- May 10 – John Ernest, Duke of Saxe-Coburg, (d. 1553)
- June 18 – Maria of Portugal, Duchess of Viseu, daughter of King Manuel I (d. 1577)
- June 21 – John II, Duke of Schleswig-Holstein-Haderslev (d. 1580)
- August 4 – Pope Urban VII (d. 1590)
- August 19 – Lodovico Guicciardini, Italian historian (d. 1589)
- October 1 – Frederick Magnus I, Count of Solms-Laubach, (d. 1561)
- November 22 – Edmund Sheffield, 1st Baron Sheffield, English baron (d. 1549)
- November 29 – Marcantonio Maffei, Italian Catholic archbishop and cardinal (d. 1583)
- December 1 – Takeda Shingen, Japanese warlord (d. 1573)
- December 13 – Pope Sixtus V (d. 1590)
- date unknown
- Anne Askew, English Protestant martyr (d. 1546)
- John Aylmer, English divine (d. 1594)
- Sue Harukata, Japanese retainer and later daimyō under Ouchi Yoshitaka (d. 1555)
- Thomas Chaloner, English statesman and poet (d. 1565)
- Philippe de Monte, Flemish composer (d. 1603)
- Rokkaku Yoshikata, Japanese daimyō (d. 1598)
- Thomas Wyatt the Younger, English rebel (d. 1554)
- March 15 – John II, Duke of Cleves (b. 1458)
- April 20 – Zhengde Emperor of China (b. 1491)
- April 24 – Spanish rebels (executed)
- April 27 – Ferdinand Magellan, Portuguese explorer (b. 1480)
- April 28 – Suzanne, Duchess of Bourbon (b. 1491)
- May 10 – Sebastian Brant, German humanist and satirist (b. 1457)
- May 17 – Edward Stafford, 3rd Duke of Buckingham (executed) (b. 1478)
- June 15 – Tamás Bakócz, Hungarian Catholic cardinal and statesman (b. 1442)
- June 21 – Leonardo Loredan, Doge of Venice (b. 1436)
- July 9 – Raffaele Riario, Italian cardinal (b. 1461)
- July – Juan Ponce de León, Spanish conquistador (b. 1460)
- August 27 – Josquin des Prez, Flemish composer (b. c. 1450)
- October 7 – Margaret of Anhalt-Köthen, Princess of Anhalt by birth, Duchess consort of Saxony (b. 1494)
- October 22 – Edward Poynings, Lord Deputy to King Henry VII of England (b. 1459)
- October 24 – Robert Fayrfax, English Renaissance composer (b. 1464)
- November 2 – Margaret of Lorraine, French Duchess of Alençon, Roman Catholic nun and blessed (b. 1463)
- December 1 – Pope Leo X (b. 1475)
- December 13 – King Manuel I of Portugal (b. 1469)
- December 21 – Domenico Spadafora, Italian Roman Catholic priest and blessed (b. 1450)
- date unknown