• Natives revolt against Spanish Rule in Nueva Galicia in what is now western Mexico, in a conflict now know as the Mixtón War. The conquest of this region by Nuño de Guzmán had been particularly brutal and the Spanish encomienda system was untenably taxing, so when when Francisco Coronado's expedition to the north leaves the garrisons low, the local peoples rise under a charismatic leader, Tenamaxtli, fortifying mountain towns such as Mixtón and Nochistlán and besieging Guadalajara. At first the regional governor, Cristóbal de Oñate, is unable to successfully counter the rebellion, lacking troops and supplies, but eventually Spanish reinforcements arrive along with a large army of Tlaxcaltec and Aztec warriors, and the towns are retaken after several bloody battles.
• Spanish conquistador Gonzalo Jiménez de Quesada completes his conquest of the Chibcha people of what is now Colombia.
• After an earthquake and several days of heavy rain, a wall of water sweeps down Mt. Agua in what is now southern Guatemala, completely destroying Ciudad Vieja and drowning over 1,000 inhabitants. The flood would later result in the founding of the town of Antigua Guatemala.
• Ottoman sultan Sulayman I invades Hungary and captures the capital, Buda, which will remain in Ottoman hands for 150 years.
• Holy Roman Emperor Charles V, seeking to check Ottoman power and build upon a successfull expedition against Tunis (1535), launches a failed attack on Algiers.
• Spanish explorer Francisco Vásquez de Coronado, on an expedition seeking the legendary Seven Cities of Cibola, sets out from his winter camp between the Rio Grande and modern-day Santa Fe to find the alleged fabulously wealthy kingdom of Quivira, guided by a Native American nicknamed "The Turk" and his fanciful tales. Journeying through the Texas Panhandle north through Oklahoma and into Kansas, Coronado finally reaches Quivira, only to find nothing more than simple Native American village, totally devoid of the promised precious metals or gems. Disillusioned, Coronado turns back for home.
• A Spanish expedition led by Hernando De Soto, sets out from Florida in search of treasure, crosses the Mississippi River and explores as far as Oklahoma before turning back.
• John Calvin returns to Geneva after three years in exile and resumes his work to create the ideal Christian city.
• Santiago, Chile is founded as Santiago de Nueva Estremadura by Pedro de Valdivia.
• Buenos Aires is abandoned and burned, by order of Domingo Martínez de Irala, after a series of attacks by natives and a severe food shortfall make the site unlivable. The colonists move to Asunción, and the site will not be resettled until 1580.
• The last Culdee community, at Armagh, is disbanded.
• Flemish cartographer Gerardus Mercator constructs the first globe of the earth.
• Swiss scientist Konrad von Gesner writes his dictionary of plants, Historia plantarum.
• German philologist Elijah Levita publishes his Talmudic dictionary, Sefer ha-Tishbi.

These people were born in 1541:

• Greek-born Spanish painter El Greco.
• Francesco de' Medici, future Grand Duke of Tuscany.
• French Catholic theologian Pierre Charron.

These people died in 1541:

• Spanish conquistador Francisco Pizarro, conqueror of Peru, surprised by a band of assassins while eating dinner. He is replaced as governor of Peru by Cristóbal Vaca de Castro.
• Spanish conquistador Pedro de Alvarado, in a foolhardy assault on the rebel town of Nochistlán.
• Doña Beatriz de la Cueva, widow of Alvarado and governor of Ciudad Vieja, in the flood.
• Tibetan mystic Gendun Gyatso, posthumously deemed the second Dalai Lama.
• Margaret Tudor, queen consort of James IV of Scotland, daughter of King Henry VII of England, and sister of Henry VIII.
• Swiss physician Philippus Aureolus Paracelsus.
• German protestant religious reformer Carlstadt.

1540 - 1541 - 1542

16th century