The interconnection between different fields of research has gained interest due to its cutting-edge perspectives in solving scientific problems. Terminalia arjuna is indigenously used in India for curing several diseases, and its pharmacological activities are being revisited in recent drug-repurposing research. Efficient ultrasound-assisted extraction of phytochemicals from the bark of Terminalia arjuna is highlighted in this study. Following the optimization of the extraction process, the crude hydroethanolic extract is subjected to phytochemical profiling and an in-silico investigation of its anti-cancer properties. A three-level four-factor Box-Behnken design is exploited to optimize four operational parameters, namely extraction time, ultrasonic power, ethanol concentration (as the extracting solvent) and solute (in g): solvent (in mL) ratio. At the optimum parametric condition, the crude extract is obtained, and its GC-MS analysis is carried out. An analysis of network pharmacology (by constructing and visualizing biological networks using Cytoscape) combined with molecular docking reveals the potential antineoplastic targets of the crude extract. The ANOVA table exhibits the significance, adequacy and reliability of the proposed second-order polynomial model with the R² value of 0.917 and adjusted R² of 0.865. Experimental results portray the significant antioxidant potential of the prepared extract in its crude form. The GC-MS analysis of the crude extract predicts the extracted phytochemicals, while the constructed biological networks highlight its multi-targeted activity in colorectal cancer. The study identifies three phytochemicals viz. luteolin, β-sitosterol and arjunic acid as potent anti-cancer agents and can be extended with in-vitro and in-vivo experiments to validate the in-silico results, thus establishing lead phytochemicals in multi-targeted colorectal cancer therapies.