The city is mentioned in Homer's Iliad as having participated in the Trojan War with thirty ships under Asclepius' sons Machaon and Podalirius.

In the Mycenean period, the city was the capital of a kingdom, and later it constituted the main center of the Thessalian region of Estaiotis, which occupied roughly the territory of the modern Trikala Prefecture.

The current name of Trikala first appears in the 11th-century Strategikon of Kekaumenos, where "Trikalitan Vlachs" are mentioned, and then in the early 12th-century Alexiad of Anna Komnene.

[4] Later in the century, the Arab traveller and geographer al-Idrisi recorded the town as "an important agrarian center with abundant vineyards and gardens" (T.E.

[4] After the dissolution of the Byzantine state by the Fourth Crusade in 1204, Trikala does not appear to have fallen into Frankish hands, but became part of the Despotate of Epirus.

[4] In the early 14th century the town was the capital of a semi-independent domain under the sebastokrator Stephen Gabrielopoulos, which extended across much of western Thessaly and Macedonia.

After his death in 1332/3 the city, along with most of Gabrielopoulos' lands, was seized by the Epirote ruler John II Orsini, but he was in turn expelled and the area incorporated into the Byzantine Empire by Andronikos III Palaiologos.

Turahan and his son and successor, Ömer Bey, erected many buildings in the city, helping it, in the words of the historian Alexandra Yerolimpos, to "[acquire] the appearance of a typical Ottoman town, with mosques, medreses, a hammam, imaret, khan and karwansaray extending beyond the citadel and the Varoussi (Varosh) quarter which remained Christian".

According to the 1603-4 "eşkal defter" Christian boys from the villages around the town were included in the batch that the Turnacıbaşı, the Chief collection officer levied.

[7] The city was largely burned down in a great fire in 1749, a destruction repeated by Albanian irregulars following an abortive uprising by the local Christian population during the Orlov Revolt.

[7] On 23 August 1881 with the Treaty of Constantinople between the Ottoman Empire and the Kingdom of Greece, the city passed in Greek sovereignty, along with the rest of Thessaly.

In the years that followed, Trikala played a fundamental role in the rural workers' mobilizations, in the early 20th century, against the Thessalian landlords (Greek: Τσιφλικάδες).

The Physical Education and Sport Science department of the University of Thessaly is also located in Trikala, and was founded in 1994, with the first students being admitted in the academic year 1994-1995; it was originally housed in the Matsopoulos Park facility, but moved to the new Karyes campus in July 1999.

Trikala has the distinction of being the first smart city in Greece, integrating new technologies into the daily life of the municipality and providing government services to citizens by means of e-governance.

Trikala's continental influence isn't enough for the city to avoid being classified as a Mediterranean climate (Csa), although with significant diurnal temperature variation.