Benzofuran and 1,3,4-oxadiazole are privileged and versatile heterocyclic pharmacophores which display a broad spectrum of biological and pharmacological therapeutic potential against a wide variety of diseases. This article reports in silico CADD (computer-aided drug design) and molecular hybridization approaches for the evaluation of the chemotherapeutic efficacy of 16 S-linkedN-phenyl acetamide moiety containing benzofuran-1,3,4-oxadiazole scaffoldsBF1–BF16. This virtual screening was carried out to discover and assess the chemotherapeutic efficacy ofBF1–BF16structural motifs asMycobacterium tuberculosispolyketide synthase 13 (Mtb Pks13) enzyme inhibitors. The CADD study results revealed that the benzofuran clubbed oxadiazole derivativesBF3,BF4, andBF8showed excellent and remarkably significant binding energies against the Mtb Pks13 enzyme comparable with the standard benzofuran-basedTAM-16inhibitor. The best binding affinity scores were displayed by 1,3,4-oxadiazoles-based benzofuran scaffoldsBF3(−14.23 kcal/mol),BF4(−14.82 kcal/mol), andBF8(−14.11 kcal/mol), in comparison to the binding affinity score of the standard referenceTAM-16drug (−14.61 kcal/mol). 2,5-Dimethoxy moiety-based bromobenzofuran-oxadiazole derivativeBF4demonstrated the highest binding affinity score amongst the screened compounds, and was higher than the reference Pks13 inhibitorTAM-16drug. The bindings of these three leadsBF3,BF4, andBF8were further confirmed by the MM-PBSA investigations in which they also exhibited strong bindings with the Pks13 of Mtb. Moreover, the stability analysis of these benzofuran-1,3,4-oxadiazoles in the active sites of the Pks13 enzyme was achieved through molecular dynamic (MD) simulations at 250 ns virtual simulation time, which indicated that these three in silico predicted bio-potent benzofuran tethered oxadiazole moleculesBF3,BF4, andBF8demonstrated stability with the active site of the Pks13 enzyme.