Zika virus (ZIKV) infection is one of the mosquito-borne flaviviruses of human importance with more than 2 million suspected cases and more than 1 million people infected in about 30 countries. There are reported inhibitors of the zika virus replication machinery, but no approved effective antiviral therapy including vaccines directed against the virus for treatment or prevention is currently available. The study investigated the chemoinformatic design and profiling of derivatives of dasabuvir, efavirenz, and tipranavir as potential inhibitors of the zika virus RNA-dependent RNA polymerase (RdRP) and/or methyltransferase (MTase). The three-dimensional (3D) coordinates of dasabuvir, efavirenz, and tipranavir were obtained from the PubChem database, and their respective derivatives were designed with DataWarrior-5.2.1 using an evolutionary algorithm. Derivatives that were not mutagenic, tumorigenic, or irritant were selected; docked into RdRP and MTase; and further subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation with Swiss-ADME and pkCSM web tools. Some of the designed compounds are Lipinski’s rule-of-five compliant, with good synthetic accessibilities. Compounds 20d , 21d , 22d , and 1e are nontoxic with the only limitation of CYP1A2, CYP2C19, and/or CYP2C9 inhibition. Replacements of −CH 3 and −NH– in the methanesulfonamide moiety of dasabuvir with −OH and −CH 2 – or −CH 2 CH 2 –, respectively, improved the safety/toxicity profile. Hepatotoxicity in 5d , 4d , and 18d is likely due to −NH– in their methanesulfonamide/sulfamic acid moieties. These compounds are potent inhibitors of N-7 and 2′-methylation activities of ZIKV methyltransferase and/or RNA synthesis through interactions with amino acid residues in the priming loop/“N-pocket” in the virus RdRP. Synthesis of these compounds and wet laboratory validation against ZIKV are recommended.