Colorectal cancer continues to impose a substantial worldwide disease burden, exceeding 1.9 million incident cases and about 900,000 deaths each year. Heat shock protein 90-beta (Hsp90β), an ATP-dependent molecular chaperone, regulates the folding and stability of numerous signaling proteins that contribute to malignant phenotypes, supporting its candidacy as a druggable target in colorectal cancer. An in silico workflow was implemented to investigate withanolides from Datura metel as putative Hsp90β inhibitors. Three withanolides (CPD1-CPD3) were docked into Hsp90β (PDB ID: 3NMQ) and benchmarked against Paclitaxel. CPD2 produced the strongest docking score (-10.19 kcal/mol), surpassing Paclitaxel (-9.67 kcal/mol), and was advanced to dynamics-based evaluation. A 100 ns molecular dynamics protocol was performed for CPD2-3NMQ and Paclitaxel-3NMQ, followed by MM/GBSA estimation using trajectory snapshots, which yielded closely similar total binding free energies (ΔTOTAL = -32.09 ± 3.73 and -32.23 ± 4.04 kcal/mol, respectively) and suggested a minor polar solvation penalty for CPD2. pkCSM-based ADMET prediction indicated complete intestinal absorption for both ligands; CPD2 showed higher predicted Caco-2 permeability and lacked P-glycoprotein substrate annotation, whereas limited aqueous solubility and several toxicity-related endpoints stated the need for optimization. Density functional theory (DFT) descriptors further characterized CPD2 with a larger energy gap (ΔE (eV)) and a slightly higher electrophilicity index (ω (eV)) than Paclitaxel. Collectively, the computational results prioritize CPD2 as a withanolide scaffold for subsequent experimental confirmation and lead refinement toward colorectal cancer therapy.