Dengue (DENV) and Zika (ZIKV) viruses are important human pathogens, causing ∼100 million symptomatic infections each year. These infections carry a 20-fold increased incidence of serious neurological diseases, such as microcephaly in newborns (for ZIKV) and Guillain-Barré syndrome. Moreover, DENV can develop serious and possibly life-threatening dengue hemorrhagic fever in certain patients. Patients recovered from one of the four serotypes of DENV are still susceptible to other serotypes with a higher likelihood of serious disease because of antibody-dependent enhancement. Except for mosquito control, there have been no antiviral drugs to prevent and treat ZIKV/DENV infections. Phenotypic screening found that 2,3,6-trisubstituted quinazolinone compounds are novel inhibitors of ZIKV replication. Fifty-four analogues were synthesized, and their structure-activity relationships are discussed. Additional testing shows that compounds 22, 27, and 47 exhibited broad and potent activities against ZIKV and DENV with EC50 values as low as 86 nM with no significant cytotoxicity to mammalian cells.