Cancer is a significant health and economic concern worldwide. Prostate cancer (PC) ranks as the fourth leading cause of global death and is the second most prevalent malignancy in males. Androgens are essential for the progress and growth of the prostate gland. PC is caused by androgens binding to receptors, which activates genes that promotes the development of PC. Nilutamide (NLM) is an antiandrogen medicine used in the treatment of PC. However, throughout treatment, it induces various toxicities and leads to resistance in patients. The objective of the work was to designed and evaluated safer NLM analogues using computational approaches with optimized pharmacokinetic profiles and less toxicity. Newer bioisosteres of the designed NLM analogues and their ADMET scores were calculated using the MolOpt and ADMETlab 3.0 tools, respectively. We conducted docking investigations of the designed ligands using AutoDock Vina software. The MolOpt web server produces 1575 bioisosteres of NLM using the scaffold transformation method. The 47 bioisosteres were selected based on pharmacokinetic profiles, drug likeness (DL) and drug score (DS) prediction scores and were determined to be optimum to excellent in comparison to NLM. The analogues NLM28, NLM31, NLM34, NLM38, NLM40, NLM44, NLM45, and NLM47 exhibited favorable interactions and docking scores with the protein (PDB ID: 2AM9). The molecular dynamics (MD) simulation results revealed that the NLM34 and NLM40 complexes were found stable during the 100 ns run. The findings indicate that the NLM analogues, particularly NLM34 and NLM40 have the potential to be used as promising antiandrogen agents for PC therapy.