In classical antiquity, the western Istria route was first used by Via Flavia in the classical antiquity, but the roads in the area declined in the Middle Ages and subsequent division of the Istrian Peninsula by the Republic of Venice and the Habsburg Empire was not conductive to development of a road system.

In the 19th century, the First French Empire started road construction, including the Trieste–Pula route now largely followed by D21.

The southernmost 2.2 kilometres (1.4 miles) of the route ran through suburbs of Pula – the largest city in the region.

D21 extended south from the Kaštel border crossing between Croatia and Slovenia situated at the Dragonja River.

[8] After the route crossed the Mirna River, it continued about six kilometres (3.7 mi) southeast to Vižinada, where D21 forms an intersection with Ž5041 county road to Kaštelir and Poreč.

Approximately nine kilometres (5.6 mi) south, at Baderna, D21 connects with D302 extending to Poreč and the A9 motorway, located west of the road junction, as well as D48 leading to Pazin east of D21.

After approximately five kilometres (3.1 mi), the route reached a grade separated intersection, a two-ramp partial cloverleaf, with D303.

It reaches a short connector to the Vodnjan-sjever (north) interchange of the A9 motorway eight kilometres (5.0 mi) down the road.

[13] In classical antiquity, the Via Flavia road built by the emperor Vespasian in 78 AD ran through the same area spanned by modern D21.

The Via Flavia followed a north–south route in the western part of the Istrian Peninsula, connecting Tergeste, present-day Trieste, to Pula via Poreč.

In Pula, the Roman road extended further to the northeast to Nesactium and Tarsatica – modern-day Trsat area of the city of Rijeka.

Road transport in the region lost significance after the peninsula was divided between the Habsburg monarchy and the Republic of Venice.

Upgrades to the regional road network continued after the Austrian Empire acquired Istria at the 1814–1815 Congress of Vienna.

[19] Since October 1991, Hrvatske ceste, a company owned by the Government of Croatia, has been tasked with maintenance of the road.

By 2002, the road lost a significant portion of its north–south traffic as A9 motorway was gradually extended since 1991,[18] running parallel to the route.