Mussolente consists of two distinct zones: a hilly area in the northern part and flatlands with an abundance of water in the southern part. For centuries, the hilly area to the north was dominant in the town's development. In the 2nd millennium BC it had been occupied by groups of shepherds and wool spinners.
Beginning in the 3rd century BC, the area gradually came under Roman domination. The demonym "Misquilesi" for the locality's residents is thought to derive from the Roman period on the basis of the inscription on a Roman soldier's tomb found in nearby Borso del Grappa referring to the "paganis misquilen" ("Misquiline people"). The period of Roman colonization coincided with increasing settlement and agricultural use of the flatlands to the south.