Zika virus (ZIKV) is among the relatively new infectious disease threats that include
SARS-CoV2, coronavirus, monkeypox (Mpox) virus, etc. ZIKV has been reported to cause severe
health risks to the fetus. To date, satisfactory treatment is still not available for the treatment
of ZIKV infection. This review examines the last five years of work using natural biomolecules
(BMs) to counteract the ZIKV through virtual screening and in vitro investigations. Virtual
screening has identified doramectin, pinocembrin, hesperidins, epigallocatechin gallate,
pedalitin, and quercetin as potentially active versus ZIKV infection. In vitro, testing has shown
that nordihydroguaiaretic acid, mefloquine, isoquercitrin, glycyrrhetinic acid, patentiflorin-A,
rottlerin, and harringtonine can reduce ZIKV infections in cell lines. However, in vivo, testing is
limited, fortunately, emetine, rottlerin, patentiflorin-A, and lycorine have shown in vivo anti-
ZIKV potential. This review focuses on natural biomolecules that show a particularly high selective
index (>10). There is limited in vivo and clinical trial data for natural BMs, which needs to
be an active area of investigation. This review aims to compile the known reference data and
discuss the barriers associated with discovering and using natural BM agents to control ZIKV
infection.