Kusquqvak (Kuskokwim river) photo from above.

The name likely comes from the deep root "ku-" (relating to flow, current, and/or liquid), -squq- (most likely an uncommon, nonproductive postbase meaning small), and -vak (meaning big). All of those together mean "big thing with small flow/current." The English word comes from the relative case use of the noun. Because the name uses a deep root and an archaic postbase, it is probably one of the older placenames in the Yup'ik language.