Garcia de Orta was born in Castelo de Vide, probably in 1501, the son of Fernão (Isaac) da Orta, a merchant, and Leonor Gomes. He had three sisters, Violante, Catarina and Isabel. Their parents were Spanish Jews from Valencia de Alcántara who had taken refuge, as many others did, in Portugal at the time of the great expulsion of the Spanish Jews by the Reyes Catolicos Ferdinand and Isabella of Spain in 1492. Forcibly converted to Christianity in 1497, they were pejoratively classed as Cristãos Novos (New Christians) and marranos ("swine"). Some of these refugees maintained their Jewish faith secretly. A friendly neighbour at Castelo de Vide was the nobleman Dom Fernão de Sousa, Lord of Labruja, who may have influenced the idea for Garcia's father to send him to University. Dom Fernão's son Martim Afonso de Sousa would become a key figure in later life.
Garcia studied medicine, arts and philosophy at the Universities of Alcalá de Henares and Salamanca in Spain. He graduated and returned to Portugal in 1525, two years after his father's death. He practiced medicine first in his home town and from 1526 onwards in Lisbon, where he gained a lecturership at the university in 1532. He also became royal physician to John III of Portugal.
Perhaps fearing the increasing power of the Portuguese Inquisition, and fortunately evading the ban on emigration of New Christians, he sailed for Portuguese India leaving Tagus in March 1534 as Chief Physician aboard the fleet of Martim Afonso de Sousa, later to be named Governor. He reached Goa in September. He travelled with Sousa on various campaigns, then, in 1538, settled at Goa, where he soon had a prominent medical practice. He was physician to Burhan Nizam Shah I of the Nizam Shahi dynasty of Ahmadnagar, and concurrently to several successive Portuguese Viceroys and governors of Goa. While Garcia de Orta was physician of the Sultan and teacher of Portuguese of his son, the Prince, he met and dined several times with the high ranking cavalry general of the Sultan, Firangi Khan. Garcia de Orta reports that the cavalry commander violated sometimes religious directives, eating pork and drinking wine in these private dinners. Firangi Khan had converted to Islam for apparently material reasons and had a very important role in the court of the Sultanate, but subsidized charities to Misericórdias in the relationship he had with the Portuguese empire (despite serving an intermittent enemy Muslim state) and, according to Orta, "urged other Christians to never abdicate their principles." He even projected return to his home city in his country (already secretly pardoned by the viceroy Afonso de Noronha). Firangi Khan was not his title (and name, which literally means "foreigner Khan") of origin. His name was Sancho Pires, a formerly gunner (bombardeiro), Portuguese, and natural of Matosinhos. He died in battle in India.
The King of Portugal through the Viceroy Dom Pedro Mascarenhas granted a lifelong lease (on payment of a quit-rent) to Garcia da Orta for the Ilha da Boa Vida ("the Island of the Good Life") which became a part of Bombay. This was probably somewhere between September 1554 and June 1555. The only condition of the lease was that he had to improve the place. He had a manor house with a large garden. He probably maintained an excellent library here. This manor stood not far from where the Town Hall of Bombay was built. Garcia probably let out the house to Simao Toscano. At the time of Bombay's transfer to the English, the manor was occupied by Dona Ignez de Miranda, widow of Dom Rodrigo de Monsanto. It was in this house that the treaty by which Bombay was transferred to the English was signed by Humphrey Cooke on February 18, 1665. Garcia describes the people around Bassein and their traditions in his book.
Contrary to some early biographical accounts, Garcia de Orta married a wealthy cousin, Brianda de Solis, in 1543; the marriage was unhappy, but the couple had two daughters. In 1549 his mother and two of his sisters, who had been imprisoned as Jews in Lisbon, managed to join him in Goa. According to a confession by his brother-in-law after his death, Garcia de Orta privately continued to assert that "the Law of Moses was the true law"; in other words, he, probably in common with others in his family, remained a Jewish believer. In 1565 an inquisitorial court was opened in Goa. Active persecution against Jews, secret Jews, Hindus and New Christians began. Garcia himself died in 1568, apparently without having suffered seriously from this persecution, but his sister Catarina was arrested as a Jew in the same year and was burned at the stake for Judaism in Goa on October 25, 1569. Garcia himself was posthumously convicted of Judaism. His remains were exhumed and burned along with an effigy in an auto da fé on December 4, 1580. They were among 342 New Christians accused of crypto-Judaism of whom 68 were executed between 1561 and 1623. His books were most likely burnt as well, possibly a reason why no copy of his book exists in Goa. The fate of his daughters is not known. During his lifetime, Orta had been protected from the Goa Inquisition by his friend and patron, Martim Afonso de Sousa, Governor-General of Portuguese India from 1542 to 1545.
Garcia de Orta's busy practice evidently prevented him from travelling much beyond the west coast of India, but in the busy market and trading hub of Goa he met spice merchants, traders and physicians from many parts of southern Asia and the Indian Ocean coasts. He was confident in Portuguese, Spanish, Hebrew, Latin, Greek and Arabic (he did not know Sanskrit); his work shows that he gathered considerable knowledge from traditional medicine practitioners from several regions of India. Correspondents and agents sent him seeds and plants; he also traded in spices, drugs and precious stones. He evidently kept a laboratory and botanical garden. De Orta was influenced by Yunnani medicine as well as Ayurveda, although quoting Galen, al-Rhazi and Ibn-Sina more often. He tended to use European approaches in medicine and only when they failed did he make use of local methods.
His remarkable knowledge of Eastern spices and drugs is revealed in his only known work, Colóquios dos simples e drogas he cousas medicinais da Índia ("Conversations on the simples, drugs and medicinal substances of India"), the first edition of which was published at Goa in 1563. This book deals with a series of substances, many of them unknown or the subject of confusion and misinformation in Europe at this period. For instance, prior to his publication, tamarind was thought to come from a palm tree. He also noted many details on plants and their propagation. He was the first European to describe the symptoms of several Asiatic tropical diseases, notably cholera; he performed an autopsy on a cholera victim, the first recorded autopsy in India. Garcia de Orta reveals in his writings an unusual independence in face of the usually revered texts of ancient authorities, Greek, Latin and Arabic. The Coloquios has 59 chapters and it was written in the style of a dialogue between da Orta and a traditional doctor, Ruano. Using a dialogue form was a common literary practice when dealing with the tensions between established and new forms of knowledge. Orta's work questions assumptions made in the past with alternative hypotheses to the ideas from Ibn-Sina and Averroes. His scientific method has been suggested to be a combination of empiricism and hypothesism.