The declining efficacies of existing drugs against estrogen receptor positive (ER+) breast cancer due to multidrug resistance, acute toxicities, and poor pharmacokinetic properties has necessitated the discovery of newer ones. In this study, colchicine analogues with proven in vitro activities against breast cancer cells were screened against estrogen receptor alpha (ERα) via molecular docking simulations to identify some promising drug candidates. The identified ligands were further subjected to MM/GBSA calculations to ascertain their solvation-dependent Gibb's free energy of binding (∆GB). Three most promising ligands (MPLs); 12, 16, and 21 with ∆GB values of - 40.37, - 40.31, and - 40.26 kcal/mol, respectively, were identified. When compared with tamoxifen (standard drug) whose ∆GB value is - 38.66 kcal/mol, the MPLs appear more potent. The kinetic stabilities of 12, 16, and 21 were confirmed by DFT (B3LYP/6-31G*) calculations and the time-dependent thermodynamic stabilities of their complexes with ERα were established by molecular dynamic simulations. In addition, the MPLs display positive pharmacokinetic and toxicity profiles and could be excellent sources of potent and non-toxic drug candidates against ER+ breast carcinoma.