Orellana arrived in the New World as reinforcements for the Pizarro clan as soon as 1535, after which he fought during the campaigns to submit the rebellious Manco Inca, in whose course Francisco lost one eye (other sources say he lost it later). When the war between the Pizarros and Diego de Almagro broke out, Orellana remained as a loyal Pizarrist, and as a reward he was appointed governor of the lands of modern day Ecuador. For several years, his job involved basically organizing the old Inca administration to fix and rebuild the collateral damage of the conquest (he even dedicated himself to learn the local languages to better coordinate things), and this only changed in 1540, when he decided join Gonzalo Pizarro's expedition in the search of the Land of Cinnamon, a fabulous land in the heart of South America where the precious spices supposedly grew freely. The expedition was possibly the largest land enterprise of the Spanish, counting on around 360 Spaniards and 4,000 natives, and carrying masses of horses, dogs, llamas and pigs to ensure success against any eventuality. Of course, if those 16th century Iberian explorations were easy, they wouldn't be 16th century Iberian explorations, as it would turn out.
Crossing the Andes turned out to be a nightmare, after which not less than 140 Spaniards and 3,000 natives had either died or deserted on the belief it would be a Suicide Mission. The unnerved Pizarro even executed their guides, believing they had conned them all, but the expedition continued anyway and eventually came upon the Coca and Napo rivers, where they built brigantines and bought canoes from friendly natives, being informed about populated villages where they could resupply. After running out of food, the explorers decided for Pizarro to wait in land with most of the expedition while Orellana continued through the Napo river with 70 men until finding the damn villages, but it took so much time for Orellana to do so that the expedition broke up: Pizarro deemed Orellana MIA and ordered to go back to the Inca lands, while Orellana and his people equally believed they were too far to rendexvous and voted to keep on the travel by themselves. Orellana and company, unsupported but undaunted, finally reached the end of the Napo and became the first Europeans to sight the largest river in the planet.
From this point, the travel became evidently such an adventure that it's hard to say what is truth and what is fiction in the chronicle of the travel. Orellana and his people apparently stopped finding friendly tribes, replaced by the hostile Omaguas and Machiparo, and had to resort to attack and plunder in order to survive, and among their enemies they supposedly found Pira-tapuya indigenous warrior women like the famed Amazons of Greek mythology, which is the reason why they named the river Amazonas (their first option had been Orellana river). In any case, after defeating the women by good ol' gunfire and keeping on with the travel without pause, the expedition finally got out of the most dense of the Amazonian jungle, and when they found tribes they could identify as Caribes, they were overjoyed to comprehend the river was finally flowing into the Atlantic coast. On August 1542, after seven grueling months of expedition, Orellana and company finally sighted the ocean, not less happy that back when the Ten Thousand sighted the Black Sea, and managed to reach the Spanish settlement of Cubagua.
Predicting that the impetuous Gonzalo would not be happy, Orellana returned directly to Spain by ship, and after rejecting an offer by King of Portugal John III to expand Brazil for them (there was some controversy whether the mouth of the Amazons belonged to Spain or Portugal by the Treaty of Tordesillas), he could personally tell King Charles V of his epic, which landed Orellana governor of all the lands he had discovered and saved him from the Pizarro family's accusations of having abandoned and betrayed them. For Orellana, that was all past history, as now he had his own feud to conquer... as well as all the troubles that come with being your own boss: politics delayed his fleet so much that he lost the king's favor, money did not arrive in time, and a family scandal broke when Francisco married the pauper, younger Ana de Ayala (apparently for love). Orellana and Ayala had to sail off hidden in his own fleet and resort to piracy to get supplies, and upon arriving in South America, they had lost half of the ships. The expedition, now reduced to 100 men, found a river mouth that Orellana identified as part of the Amazonas delta.
Sometimes, what starts badly ends even worse, and this second expedition would be not only unsuccessful, but also Orellana's final. After weeks of walking in circles around the lands in the search of the mouth river, being attacked by natives, eating all of their food and just plain going insane, Orellana died, according to Ayala by a mix of illness and desperation. Only 46 expeditioners survived, led by Ayala and Diego García de Paredes Jr (the son of Diego García de Paredes) to the nearby settlement of Margarita Island, from which most of them embarked in the search of more fortunate conquests through America.
- Aguirre, the Wrath of God features the disappeared expedition of Orellana at the background, and a cut subplot would have addressed it directly.
- Orellana is mentioned at the background of Indiana Jones and the Kingdom of the Crystal Skull.
- La conquista del Amazonas is a historical novel about Orellana written by Spanish-British actor Edward Rosset.
- Orellana is featured in the El Dorado expansion of Age of Empires II.
- He also appears in The Amazon Trail.