The 1500s ran from January 1, 1500, to December 31, 1509.
- July – Ismail I is enthroned as Shah of Azerbaijan, choosing Tabriz as his capital, founding the Safavid Dynasty in northern Iran. He declares Shi'ism the official and compulsory religion, under penalty of death.
- July 21 – Portuguese explorer Pedro Cabral returns to Lisbon, from his expedition to Calicut (Nicolau Coelho having arrived on June 23).
- July 27 – Copernicus is formally installed, as canon of Frauenberg Cathedral.
- August 27 – Battle of the Siritsa River: The Livonian Order, supporting the Grand Duchy of Lithuania in the Second Muscovite–Lithuanian War, and commanded by Wolter von Plettenberg, defeats an army of the Grand Duchy of Moscow and Pskov Republic.
- October 13 – Treaty of Trente: Maximilian of Austria and Louis XII of France sign the treaty, with Austria recognizing all French conquests in the northern territories of Italy.
- October 30 – The Banquet of Chestnuts is purportedly held by Cesare Borgia, in the Papal Palace of Rome (this account is not historical fact, and could be attributed to enemies of Alexander VI).
- November 1 (All Saints) – Amerigo Vespucci discovers and names Baía de Todos os Santos, in Brazil.
- November 4
- November 12 – Sten Sture the Elder is elected Regent of Sweden for the second time.
- November 14 – Arthur, Prince of Wales, marries the Spanish princess Catherine of Aragon.
- November 24 – A large army of the Grand Duchy of Moscow overruns Livonia during the Second Muscovite–Lithuanian War.
- December 12 – Alexander Jagiellon becomes King of Poland.
- January 1 – Portuguese explorers, led by Gonçalo Coelho, sail into Guanabara Bay, Brazil, mistaking it for the mouth of a river, which they name Rio de Janeiro.
- February 12 – Isabella I issued an edict outlawing Islam in the Crown of Castile, forcing virtually all her Muslim subjects to convert to Christianity.
- May 3 – Portuguese navigator João da Nova discovers the uninhabited island of Saint Helena.
- May 11 – Christopher Columbus leaves Cadiz, Spain for his fourth and final trip to the New World. He explores Central America, and discovers St. Lucia (possibly), the Isthmus of Panama, Honduras, and Costa Rica.
- The first African slaves brought to the New World arrive at the island of Hispaniola (modern-day Haiti and Dominican Republic).
- Bristol merchants return from Newfoundland (first so named this year from a letter) to England, carrying three native people and cod from the Grand Banks.
- Moctezuma II is elected emperor of the Aztecs, following the death of Ahuitzotl.
- Meñli I Giray defeats the Golden Horde and sacks their capital, Sarai.
- Wittenberg University is founded.
- In Germany, Peter Henlein of Nuremberg uses iron parts and coiled springs to build a portable timepiece.
- In Italy, Asher Lämmlein declares that the Jewish Messiah will arrive in the next 6 months, resulting in the year of penance.
- The King's School, Macclesfield, England, is founded by Sir John Percyvale.
- Heinrich Cornelius Agrippa receives the degree of magister artium from the University of Cologne.
- Wilhelm Bombast moves to Villach with his son, Paracelsus.
- January 20 – Seville in Castile is awarded exclusive rights to trade with the New World.
- January 24 – Construction of the Henry VII Chapel at Westminster Abbey begins in the perpendicular style, the final stage of English Gothic art.
- February 11 – Queen Elizabeth of York, wife of Henry VII of England, dies on her 37th birthday, more than a week after giving birth to her daughter Katherine Tudor, who died the previous day.
- February 13 – Challenge of Barletta: Thirteen Italian knights defeat thirteen French knights, near Barletta.
- February 23 – French–Spanish Wars in Italy – Battle of Ruvo: The Spanish defeat the French.
- April 21 – Battle of Seminara: Spanish forces under Fernando de Andrade de las Mariñas defeat the French under Bernard Stewart, 4th Lord of Aubigny.
- April 28 – Battle of Cerignola: Spanish forces under Gonzalo Fernández de Córdoba defeat the French under Louis d'Armagnac, Duke of Nemours, who is killed (considered to be the first battle in history won by gunpowder small arms).
- May 10 – Christopher Columbus discovers the Cayman Islands, which he names Las Tortugas, after the numerous sea turtles there.
- May 13 – Naples is captured by the Spanish.
- May 20 (Feast of the Ascension) – Ascension Island is first definitively sighted, by Portuguese admiral Afonso de Albuquerque.
- May 28
- July 23 – Orbital calculations suggest that on this day, Pluto moves outside Neptune's orbit, remaining there for 233 years.
- July 30 – Saint Helena is first definitively sighted, by ships of Portuguese navigator Estêvão da Gama returning from the East.
- August 8 – King James IV of Scotland marries Margaret Tudor, daughter of King Henry VII of England, at Holyrood Abbey, Edinburgh, Scotland.
- August 20 – Stephen III of Moldavia concludes a treaty with Sultan Bayezid II, preserving Moldavia's self-rule at the cost of an annual tribute to the Ottoman Empire.
- September 22 – Pope Pius III (Francesco Todeschini Piccolomini) succeeds Alexander VI as the 215th pope, but dies on October 18.
- October 30 – Queen Isabella I of Spain prohibits violence against indigenous peoples in the New World.
- October 31 – Pope Julius II succeeds Pius III, as the 216th pope (some sources list November 1 as the date of election).
- December 29 – Battle of Garigliano, near Gaeta, Italy: Spanish forces under Gonzalo Fernández de Córdoba defeat a French–Italian mercenary army under Ludovico II, Marquess of Saluzzo; the French forces withdraw to Gaeta.
- September 8 – Michelangelo's sculpture of David is completed in Florence.
- September 13 – Queen Isabella and King Ferdinand issue a Royal Warrant for the construction of Capilla Real, a Royal Chapel, to be built.
- September 22 – A settled engagement is arranged, between Karel of Luxembourg and Claudia the Beaujeu.
- September 22 – Treaty of Blois: Philip I of Castile, Maximilian I and Louis XII agree to terms.
- October 12 – Isabella I of Castile signs her testament.
- November 7 – Christopher Columbus returns to Spain from his fourth voyage, during which he and his younger son, Ferdinand, explored the coast of Central America from Belize to Panama.
- November 26 – Isabella I of Castile, Catholic Queen of Castile and Aragon, dies, ending her patronage for Columbus. The Crown of Castile passes to her daughter Joanna.
- December 8 (approximate date) – Islamic scholar Ahmad ibn Abi Jum'ah issues the Oran fatwa for Muslims in Spain (1 Rajab 910 AH in Hijri calendar, Gregorian date is approximate).
- December 24 – The Alvsson's rebellion was crushed at Olsborg Castle in Båhuslen.
- Babur besieges and captures Kabul.
- Islamization of the Sudan region: A Funj leader, Amara Dunqas, founds the Sultanate of Sennar.
- Sheikh Ahmad, final leader of the Great Horde, is last heard of as a Lithuanian prisoner at Vilnius.
- Juan de la Cosa begins his first independent voyage, to the Isthmus of Panama.
- In Florence, Leonardo da Vinci and Niccolò Machiavelli become involved in a scheme to divert the Arno River, cutting the water supply to Pisa to force its surrender: Colombino, the project foreman, fails to follow da Vinci’s design, and the project is a major failure.
- Venetian ambassadors suggest to Turkey the construction of a Suez Canal.
- Aldus Manutius publishes his edition of Demosthenes in Venice.
- Matthias Grünewald paints a Crucifixion.
- The Signoria of Florence commissions both Leonardo da Vinci and Michelangelo to paint the walls of the Grand Council Chamber in the Palazzo Vecchio.
- Raphael paints The Marriage of the Virgin, which exemplifies some major principles of High Renaissance art.
- July 2 – Martin Luther, aged 22, vows to become a monk in a moment of terror, due to a near lightning strike during a thunderstorm, near the village of Stotternheim.
- July – The Kalmar Bloodbath takes place in Kalmar, Sweden.
- July 17 – Luther enters the monastic life, at an Augustinian cloister in Erfurt.
- July 24 – Travelling to India, a group of Portuguese explorers sack the city-state of Kilwa in East Africa, killing the king for failing to pay tribute.
- November 6 – Vasili III succeeds Ivan III, as Grand Prince of Muscovy.
- December 18 – John IX van Horne, prince-bishop of Liège, Belgium, is executed.
- A Portuguese fleet attacks Kilwa, and then Mombasa. The Portuguese then attempt to monopolize the trade in the east African ports, but are unable to maintain control (by the late 16th century, Swahili groups regain control of several ports from the Portuguese).
- Portuguese merchants establish factories on the east coast of Africa.
- Portuguese explorers under Dom Lourenço d'Almeida reach Colombo on Sri Lanka and send envoys to the King of Kotte; they also reach the Comoros.
- Bermuda is discovered by Spanish explorer Juan de Bermúdez.
- King Alexander of Poland signs the Nihil novi Act, making Poland a Nobles' Democracy.
- Poland prohibits peasants from leaving their lands, establishing serfdom.
- Christ's College, Cambridge, England, is re-founded, receiving its charter from Lady Margaret Beaufort.
- Judah Abravanel becomes personal physician to the viceroy of Naples.
- Battle of Achnashellach in Scotland: The Clan Cameron emerges victorious over several other clans.
- Watch 1505, the earliest known pocket watch, is made at Nuremberg, Germany by Peter Henlein.
- 1505 (or 1506) – Portuguese explorer Gonçalo Álvares is the first to sight what will later be known as Gough Island in the South Atlantic.