The town's area has been populated from prehistoric times, and prehistoric flint tools were found in the modern town's area. In Roman times, a way-station existed in the location called Cala-c'Aliya. Invading armies, many of which came from the Mediterranean coast just 12 km away, often came through Qalqilyah. Its current name comes from the Arabic Qala'alia, meaning high fortress. During the subsequent Muslim rules of the area, the town was populated with Arab inhabitants.
Following the Oslo Accords, the town came under the jurisdiction of the Palestinian Authority. Since 2003, the Israeli Separation Wall has been built to completely encircle Qalqilyah, separating the city from agricultural lands on the other side of the wall, leading to anger and protests from many of the citizens of the city.