Zika virus (ZIKV) is an emerging mosquito-borne virus that now circulates in many regions of the world. ZIKV infection causes severe damage to the brain development of fetuses and neurological complications in adult patients. The ZIKV transmission routes in humans involves not only the mosquito bite but also the contact to body fluids from infected people. Nowadays, we are still lacking of effective disease prevention measures against Zika disease. Some broad-spectrum drugs are not suitable for use against ZIKV because they can be harmful to pregnant women. Secondary metabolites produced by plants, such as alkaloids, coumarins, curcuminoids, flavonoids, terpenoids, polyphenolics, and saponins, remain a remarkable safe and effective naturally derived substances against ZIKV. These phytochemicals are able to interfere both in the early stages of viral infectious cycle and in the late stages. Here a comprehensive overview of the recent advances of viral molecular tools allows the identification of naturally derived anti-ZIKV compounds.