Flaviviruses, such as Dengue (DENV), West Nile (WNV) and Zika (ZIKV) viruses are transmitted to humans mainly by the bite of mosquitos and are a serious public health treat. Despite the global spread and disease severity, there is no specific and effective treatment, in part due to a poor understanding of the flavivirus life cycle. The capsid (C) protein, conserved in terms of sequence and structure among flaviviruses, is a major drug target. For example, DENV C mediates viral life cycle, namely by binding to host lipid droplets (LD), which is essential for viral replication. Here, we investigated WNV and ZIKV C protein binding to host lipid systems. Zeta potential shows that WNV C interacts with LD surface proteins, requiring K+ ions, as previously shown for DENV C by us. ZIKV C also binds to LD, although in this case Na+ and K+ ions are interchangeable. Dynamic light scattering shows that WNV C binds very low-density lipoproteins (VLDL) but not low-density lipoproteins (LDL). ZIKV C also binds to VLDL, similarly to DENV C. Following, WNV C (un)binding forces upon interaction with LD and VLDL were determined by atomic force microscopy (AFM)-based force spectroscopy. AFM confirmed that WNV C binds specifically to LD and VLDL (but not LDL), in a process requiring K+ ions. Furthermore, ZIKV, WNV and DENV C protein sequences display similar predicted hydrophobicity, α-helical propensity and tertiary structure that can thus be targeted via similar approaches. Combining all this with our background on DENV C protein and pep14-23 peptide (an inhibitor of DENV C binding to host lipid systems, designed and patented by us), we will now use this information for Flavivirus drug development strategies.