| 1458 | Joanes de Antxieta, musician to the Court of the Catholic Monarchs, is born in Azpeitia. | 1452 | Birth of Leonardo da Vinci, greatest exponent of the Renaissance as an attempt to achieve universal knowledge. |
| 1468 | The shepherd Rodrigo de Baltzategi claims to have seen an apparition of the Virgin Mary on a thorn bush (Arantzazu). | 1478 | The Catholic Monarchs create the Spanish Inquisition. |
| 1492 | Sailors from Gipuzkoa participate in Columbus' first expedition to the Americas. | 1492 | Capture of Granada and expulsion of the Jews from all the kingdoms of the Peninsula. |
| 1498 | A fire destroys Hondarribia, leaving only 9 houses standing. The use of stone and other measures is encouraged in the towns of Gipuzkoa. | 1498 | The Portuguese Vasco de Gama reaches India by coasting Africa: the Silk Road, under Turkish control, is no longer the only route for Asian products. |
| 1522 | Juan Sebastián Elcano, from Getaria, leads the first expedition to circumnavigate the globe. | 1517 | Luther criticises the Church and publishes his Theses: birth and expansion of Protestantism. |
| 1527 | First documentary record of Gipuzkoan ships in Terranova. | 1530 | Final division of Navarre into two kingdoms, following the conquest of peninsular Navarre by Castile. |
| 1540 | Start of construction on the Igartubeiti baserri-press: thousands of baserris are built following this model, at a time of economic growth in Gipuzkoa. | 1540 | The Pope ratifies the foundation of the Company of Jesus, a bastion of the Catholic Counterreformation in Europe and a vehicle for evangelisation in Asia and America. |
| 1555 | Major victory of Gipuzkoa against the French privateers, despite a balance of one thousand Gipuzkoan sailors killed in three years. | 1542 | Fray Bartolomé de las Casas denounces the Castilian exploitation of the indigenous peoples of America: although he manages to have laws passed banning their enslavement, his actual success is limited. |
| 1561 | Lope de Aguirre, the Oñati-born Amazonian explorer, declares himself a traitor to King Philip II. | 1560 | Juana de Albret, queen of Lower Navarre, converts to Calvinism and encourages the translation of the Bible into Basque. |
| Towards 1565 | Gonzalo de Perkaiztegi, born in Hernani, introduces maize to the Basque country. | 1564-67 | Perez de Lazarraga, from Alava, writes several poems and a pastoral novel in Basque, in the Renaissance style. |
| 1567 | The territory of Gipuzkoa, as far as San Sebastián and the valley of Baztan-Bidasoa in Navarre, are transferred from the diocese of Bayonne to the diocese of Pamplona. | 1568 | The Protestant-majority Low Countries rebel against Philip II: this is the start of an 80-year war that ends with their full independence. |
| 1588 | Major economic activity at the shipyards of Pasaia to replace the ships lost in the "Spanish Armada". | 1584 | One of the territories of North America is named Virginia in honour of Elizabeth I, "the Virgin Queen": England has become a major military and economic power. |