Kyasanur forest disease (KFD) is a zoonotic disease that is endemic to southern India and caused by KFD virus (KFDV) belonging to the family Flaviviridae. Humans are the dead-end host of the KFDV life cycle. The absence of effective treatment strategies against KFD can be attributed to a lack of studies on the mechanistic part of the spread of the disease. Hypothesizing molecular etiological similarity of KFDV to other well characterized flaviviruses, such as dengue virus (DENV), we focused on predicting the target receptor protein(s) in host and provided molecular basis of receptor-mediated recognition of the human host by KFDV envelop protein (EKFDV), drawing from the extant knowledge on the dengue counterpart, EDENV. Indeed, in silico approach helped to identify that the EKFDV structure closely resembles the EDENV structure and indicated DC-SIGN and/or Mannose receptors to be the plausible target host receptors. Immune-informatics approach aided in predicting 10 epitopes from E, NS1, NS2A, and NS2B proteins of the KFDV-P9605 genotype for vaccine design against KFDV. Further, molecular dynamics simulation (MDS) analyses of their complexes with human leukocyte antigens (HLAs) identified the epitopes DISLTCRVT and YAMEIRPVH as two high ranking candidates for vaccine design. Communicated by Ramaswamy H. Sarma. © 2023 Informa UK Limited, trading as Taylor & Francis Group.