Flaviviruses have been important human pathogens after emerging and resurging flavivirus diseases over the past decades. Although effective therapeutic agents are not yet commercially available for use in humans, significant progress has been made toward developing effective therapeutics and treatments. Several studies have shown that antibodies against the flaviviral E and NS1 proteins play a central role in prophylaxis and/or treatment of flavivirus infection through passive immunization. In addition, many anti-flavivirals, including interferons, oligonucleotide-based platforms, and small compounds, have been developed and evaluated for their antiviral effects. This review provides an overview of various approaches to the development of anti-flaviviral candidates and new insights that could improve our strategies for designing effective therapeutics against flaviviruses.