Overexpression of Cytochrome P450 1B1 in malignancies is accountable for the biotransformation-based inactivation of various chemotherapeutics such as docetaxel, paclitaxel, cisplatin, and tamoxifen. Additionally, it also plays a major role in the development of metabolic disorders including cancer progression, diabetes, obesity, glaucoma, fatty liver, etc. This makes CYP1B1 a unique target. Currently, numerous small molecule inhibitors of CYP1B1 are being explored to prevent cancer progression and drug resistance problems to the above-mentioned chemotherapeutics. In the current study, several benzoxazolinone derivatives have been designed and explored as CYP1B1 inhibitors using various in-silico approaches including molecular docking, molecular dynamics (MD), and waterswap analysis. Molecular docking studies revealed that all the designed compounds mimic the crucial active site interactions of co-crystal ligand i.e. Alpha naphthoflavone (ANF). To understand the interaction stability of the top four docked compounds a 100ns MD analysis was performed. Furthermore, binding free energies of the top docked molecules were computed using three different free energy algorithms such as Bennet, Thermodynamic integration (TI), and free energy perturbation (FEP). The proposed compounds were tested for inhibitory activity towards CYP1B1 using EROD assay. Among all, compounds R-7 and R-8 were found to be the most promising potent CYP1B1 inhibitors with IC50 values of 0.06 and 0.09 µM respectively. This research shows that the reported compounds could be used as possible adjuvants with resistance-reversing properties, potentially improving cancer therapy quality.