Kozhikode was the capital of an independent kingdom ruled by the samoothiris (Zamorins) in the Middle Ages and later of the erstwhile Malabar District under British rule. Arab merchants traded with the region as early as 7th century, and Portuguese explorer Vasco da Gama landed at Kozhikode on 20 May 1498, thus opening a trade route between Europe and Malabar. A Portuguese factory and the fort was intact in Kozhikode for short period (1511–1525, until the Fall of Calicut). The English landed in 1615 (constructing a trading post in 1665), followed by the French (1698) and the Dutch (1752). In 1765, Mysore captured Kozhikode as part of its occupation of the Malabar Coast. Kozhikode, once a famous cotton-weaving centre, gave its name to the Calico cloth. Vasco da Gama's arrival in Calicut in 1498 ushered in five centuries of rule of the Portuguese Empire in India, lasting until 1961. It was ranked eleventh among Tier-II Indian cities in job creation by a study conducted by ASSOCHAM in 2007.

Ibn Battuta (1342–1347), who visited six times, gives the earliest glimpses of life in the city. He describes Kozhikode as "one of the great ports of the district of Malabar" where "merchants of all parts of the world are found here". The king of this place, he says, "shaves his chin just as the Haidari Fakeers of Rome do... The greater part of the Muslim merchants of this place are so wealthy that one of them can purchase the whole freightage of such vessels put here and fit out others like them".

Ma Huan (1403 AD), the Chinese sailor part of the Imperial Chinese fleet under Cheng Ho (Zheng He) lauds the city as a great emporium of trade frequented by merchants from around the world. He makes note of the 20 or 30 mosques built to cater to the religious needs of the Muslims, the unique system of calculation by the merchants using their fingers and toes (followed to this day) and the matrilineal system of succession.

Abdur Razzak (1442–43) the ambassador of Persian Emperor Sha-Rohk finds the city harbour perfectly secured and notices precious articles from several maritime countries especially from Abyssinia, Zirbad and Zanzibar.

The Italian Niccolò de' Conti (1445), perhaps the first Christian traveller who noticed Kozhikode, describes the city as abounding in pepper, lac, ginger, a larger kind of cinnamon, myrobalans and zedary. He calls it a noble emporium for all India, with a circumference of 13 kilometres (8 miles).

The Russian traveller Athanasius Nikitin or Afanasy Nikitin (1468–74) calls 'Calecut' a port for the whole Indian sea and describes it as having a "big bazaar."

Other travellers who visited Kozhikode include the Italian Ludovico di Varthema[21] (1503–1508) and Duarte Barbosa. 

The Samoothiri

Kozhikode and its suburbs formed part of the Polanad kingdom ruled by the Porlatiri. The Eradis of Nediyiruppu at Kondotty in Eranad wanted an outlet to the sea, to initiate trade and commerce with the distant lands. and after fighting with the king Polatthiri for 48 years conquered the area around Panniankara. After this, Menokki became the ruler of Polanad and came to terms with the troops and people. After this, the town of Kozhikode was founded close to the palace at Tali. Then, the Eradis shifted their headquarters from Nediyiruppu to Kozhikode. The Governor of Ernad built a fort at a place called Velapuram to safeguard his new interests. The fort most likely lent its name to Koyil Kotta the precursor to Kozhikode. Thus the city came into existence sometime in the 13th century CE. The status of Udaiyavar increased and he became known as Swami Nambiyathiri Thirumulpad, and eventually Samuri or Samoothiri. Europeans called him in a corrupt form as Zamorin.

According to K.V. Krishna Iyer, the rise of Kozhikode is at once a cause and a consequence of Samoothiri's ascendancy in Kerala. By the end of the century, Samoothiri was at the zenith of his powers with all princes and chieftains of Kerala north of Kochi acknowledging his suzerainty.