Effective chemotherapy is essential for controlling malaria. However, resistance of Plasmodium falciparum to existing antimalarial drugs has undermined attempts to control and eventually eradicate the disease. In this study, a series of 2-((substituted)(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against P. falciparum. The development of synthesized compounds (F1-F16) was justified through the study of H1 NMR, C13 NMR, mass spectra. Compound F1 and F2 were also structurally validated by single crystal X-ray diffraction analysis. All the compounds were evaluated for their in vitro antiplasmodial assessment against the W2 strain (chloroquine-resistant) of P. falciparum IC50 values ranging from 0.74-6.4 microM. Two compounds, F4 and F16 exhibited significant activity against W2 strain of P. falciparum with 0.75 and 0.74 microM. The compounds (F3-F6 and F16) were also evaluated for in vitro cytotoxicity against two cancer cell lines, human lung (A549) and cervical (HeLa) cells, which demonstrated non-cytotoxicity with significant selectivity indices. In addition, in silico ADME profiling and physiochemical properties predicts drug-like properties with a very low toxic effect. Thus, all these results indicate that tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine scaffolds may serve as models for the development of antimalarial agents.