Significance Hepatitis C virus (HCV) is a pervasive human pathogen for which a vaccine is urgently needed. Vaccine development relies on inducing neutralizing antibodies (NAbs), but HCV employs complex mechanisms to evade neutralization that remain incompletely understood. Here, we discover a unique interplay between two separate molecular features of HCV envelope protein E2, the hypervariable region 1 and N-linked glycans, that protect HCV from NAbs. Furthermore, we find that they share a mechanism in which they broadly modulate NAb epitope availability by influencing stability of closed and open envelope protein conformations (e.g., envelope breathing) and virus entry dependency on scavenger receptor BI. The apparent importance of structural dynamics in understanding HCV NAb evasion and entry have important implications for rational vaccine design.