[1] It is notable as the site of Alexander the Great's city Alexandria on the Oxus, as a center of early Buddhism, as a site of Muslim pilgrimage, and as a base of Soviet Union military operations in Afghanistan, accessible via the nearby Hairatan border crossing.

Some link the name of the city to the Greek word Θέρμος (thermos), meaning "hot", and date the toponym to the rule of Alexander the Great.

[4][5] One of Central Asia's oldest towns, Old Termez, located a few kilometers west of the modern city along the Amu Darya river, was established sometime before the 3rd century BC.

[6] The city may have been known to the Achaemenids (the 10th century Shahnameh purports its existence during the mythological Zoroastrian Kayanian dynasty).

[9] It was during this period that Termez, named Ta-li-mi (迭里迷) in Chinese sources, became an important center of Mahāsāṃghika Buddhism.

[10][11] Termez was incorporated into the Sassanid Persian Empire in the 3rd century AD, and elements of Zoroastrian-Buddhist religious syncretism appear in the archaeological record, with Buddhist monasteries containing fire altars,[12] and a graffiti inscription referencing "Buddha-Mazda.

The stupas and the images of the honoured Buddha are noted for various spiritual manifestations.In the three decades that followed, as the Umayyads conquered the Persians, Termez found itself across the river from the caliphate.

"[16][17] Ibn Battuta found the city reconstructed in the early 14th century: We set out from Samarqand and reached Tirmidh [Termez], a large town with fine buildings and bazaars and traversed by canals.

The old town of Tirmidh was built on the bank of the Oxus, and when it was laid in ruins by Tinklz [Chingiz] this new town was built two miles from the river.The restored Termez soon came under the rule of Tamerlane's Timurid Empire with the backing of the Tirmidh Sayyids, a local religious aristocracy claiming descent from Muhammad through Sayyid Ali Akbar.

By the second half of the 18th century the city was again abandoned, and the ruins of the reconstituted Termez laid outside the nearby villages of Salavat and Pattakesar (Pattagissar).

In 1887, the Russian Empire began to operate a brown water navy on the Amu Darya River.

[21] During the years of Soviet rule, as Termez became a hub of Russian military activity, many industries were developed, and a pedagogical institute and a theatre were opened.

The military airfield was the main support base for German and Dutch forces operating with the ISAF for transiting goods into Afghanistan.

[24] Following the 2021 Taliban offensive and resultant Fall of Kabul, the Biden administration reached out to Uzbekistan, as well as Kazakhstan and Tajikistan, to ask if they might temporarily accommodate up to 9,000 Afghans who might face reprisals for working with U.S. military forces.

Plans exist to connect Termez to Peshawar by rail, as a part of the China–Pakistan Economic Corridor, and China's larger Belt and Road Initiative.

Termez river port (Termiz daryo bandargohi) is located in the south-eastern part of the city.

Using satellite data, Termez was classified as a "Type 3" city, having a "Growing Population & Declining Economic Activity.