February 2 – Battle of Baçente: The Portuguese under Cristóvão da Gama capture a Moslem-occupied hillfort in northern Ethiopia.
February 13 – Catherine Howard, the fifth wife of Henry VIII of England, is executed for adultery.
February 14 – Guadalajara, Mexico, is founded by the Spaniards after 3 previous attempts failed, due to aggressive opposition from local tribes.
March 8 – Antoine Escalin des Eymars, the French ambassador, returns from Constantinople with promises of Ottoman aid in a war against Charles V, Holy Roman Emperor.
April 4–16 – Battle of Jarte in Ethiopia: The Portuguese under Cristóvão da Gama encounter the army of Imam Ahmad Gragn and inflict upon him two successive defeats.
May 19 – The Prome Kingdom, in modern-day central Burma, is conquered by the Taungoo Dynasty.
July 12 – Charles V, Holy Roman Emperor declares war on King Francis I of France. This time King Henry VIII of England is allied to the Emperor, while James V of Scotland and Sultan Suleiman I are allied to the French.
August – Battle of the Hill of the Jews: During the rainy season, Cristóvão da Gama captures a strategic position and many badly-needed horses.
August 24 – Battle of Haddon Rig: Scotland defeats England.
August 27 – Citizens of Hildesheim in the Holy Roman Empire profess themselves to the Lutheran teachings. As a pledge owner, the city provides for the carrying out of the Protestant Reformation in the city and Peine. Priests from the localities of Clauen, Hohenhameln, Soßmar, Schmedenstedt, Lengede and Rosenthal resume their offices in the interest of the Reformation.
August 28 – Battle of Wofla in Ethiopia: Reinforced with at least 600 arquebusiers and cavalry, Imam Ahmad Gragn attacks the Portuguese camp. The Portuguese are scattered; Cristóvão da Gama is captured and executed.
September 4 – Earliest recorded Preston Guild Court in Lancashire, England, in the modern sequence, which lasts unbroken until 1922.
September 28 – Portuguese explorer Juan Rodríguez Cabrillo lands in what is now San Diego Bay and names it "San Miguel"; it will later become the city of San Diego.
October 7 – Cabrillo becomes the first European to set foot on Santa Catalina Island, California.
November 24 – Battle of Solway Moss: An English army invades Scotland and defeats a Scottish army.
December 14 – Mary, Queen of Scots, becomes queen regnant at the age of only one week on the death of her father, James V of Scotland.
The first contact of Japan with the West occurs when a Portuguese ship, blown off its course to China, lands Fernão Mendes Pinto, Diogo Zeimoto and Cristovão Borralho in Japan.
Pope Paul III establishes the Holy Office with jurisdiction over the Roman Inquisition.
Bartolomé de las Casas completes A Short Account of the Destruction of the Indies, which would be published in 1552.
February 1 – John Scudamore, English politician (d. 1623)
February 22 – Santino Garsi da Parma, Italian musician (d. 1604)
March 19 – Jan Zamoyski, Polish nobleman (died 1605)
April 29 – Henry III, Duke of Münsterberg-Oels (d. 1587)
May 5 – Thomas Cecil, 1st Earl of Exeter, English politician (d. 1623)
May 11 – Jakob Christoph Blarer von Wartensee, Roman Catholic bishop (d. 1608)
May 16 – Anna Sibylle of Hanau-Lichtenberg, German noblewoman, daughter of Count Philip IV of Hanau-Lichtenberg (d. 1580)
June 15 – Richard Grenville, English politician (d. 1591)
June 24 – John of the Cross, Spanish Carmelite mystic, theologian, poet (d. 1591)
July 25 – Magnus, Duke of Östergötland, Swedish prince (d. 1595)
August 18 – Charles Neville, 6th Earl of Westmorland (d. 1601)
August 27 – John Frederick, Duke of Pomerania and Protestant Bishop of Cammin (d. 1600)
August 31 – Isabella de' Medici, Italian princess (d. 1576)
September 25 – Elisabeth of Nassau-Dillenburg, Sister of William the Silent (d. 1603)
Mariam-uz-Zamani, Mughal Empress (d. 1623)
Álvaro de Mendaña de Neira, Spanish explorer (d. 1595)
June 6 – Richard Grenville, Elizabethan soldier and explorer (died 1591)
October 4 – Robert Bellarmine, Italian saint (died 1621)
October 14 – Philip IV, Count of Nassau-Weilburg (d. 1602)
October 15 – Akbar, Mughal Emperor (died 1605)
October 31 – Henriette of Cleves, Duchess of Nevers, Countess of Rethel (d. 1601)
November 1 – Tarquinia Molza, Italian singer (d. 1617)
November 9 – Anders Sørensen Vedel, Danish historian (d. 1616)
November 11 – Scipione Gonzaga, Italian cardinal (d. 1593)
December 8 – Mary, Queen of Scots (died 1587)
December 21 – Thomas Allen, Mathematician (d. 1632)
Toda Kazuaki, samurai in the service of Tokugawa Ieyasu (died 1604)
John Speed, English historian (died 1629)
Horio Yoshiharu, Japanese daimyo (died 1611)
Kuki Yoshitaka, Japanese naval commander (died 1600)
February – Nikolaus Federmann, German adventurer in Venezuela and Colombia (born 1501)
February 1 – Girolamo Aleandro, Italian cardinal (born 1480)
February 13 – Catherine Howard, Fifth Queen of Henry VIII of England (executed) (born c. 1522)
March 3 – Arthur Plantagenet, 1st Viscount Lisle, illegitimate son of King Edward IV of England
May 21 – Hernando de Soto, Spanish explorer, navigator and conquistador (born c. 1500)
June 19 – Leo Jud, Swiss reformer (born 1482)
July 15 – Lisa del Giocondo, believed to be the subject of the Mona Lisa
August 24 – Gasparo Contarini, Italian diplomat and cardinal (born 1483)
August 29 – Cristóvão da Gama, Portuguese soldier (born c. 1516)
September 21 – Juan Boscán Almogáver, Spanish poet (born c. 1490)
October 11 – Thomas Wyatt, English poet and diplomat (born 1503)
December 14 – King James V of Scotland (born 1512)
Dosso Dossi, Italian painter (born 1490)
Lucas Fernández, Spanish dramatist and musician (born c. 1474)
Lapu-Lapu, Filipino king (born 1491)
Year 1542 (MDXLII) was a common year starting on Sunday (link will display the full calendar) of the Julian calendar.