<p>A simple, precise, environmentally friendly, and selective high-performance thin-layer chromatography (HPTLC) method has been developed and validated for the simultaneous quantification of axitinib, pazopanib hydrochloride, crizotinib, ruxolitinib, and ibrutinib in bulk and pharmaceutical dosage forms. These five anticancer drugs are commonly utilized in the treatment of various malignancies and have demonstrated superior efficacy when used in combination therapies compared with monotherapy. This allows for dosage reduction and, consequently, a decrease in toxicity. The drugs were effectively separated on silica gel HPTLC plates (G60 F₂₅₄) using a mobile phase comprising methanol–0.1% formic acid (65:35, <i>V/V</i>), with ultraviolet (UV) detection at 268 nm under ambient conditions. Experimental parameters were optimized, yielding linearity ranges of 5–50&#xa0;µg per band for axitinib and pazopanib; 10–60 µg per band for ruxolitinib and ibrutinib; and 10–50 µg per band for crizotinib, demonstrating high sensitivity and low limits of detection: 0.052, 0.066, 0.111, 0.093, and 0.038 µg per band for axitinib, pazopanib, ruxolitinib, ibrutinib, and crizotinib, respectively. The method was successfully applied to the separation of these drugs in both bulk and dosage forms, yielding high recovery rates, which confirm the efficiency of the approach. Additionally, the greenness of the method was evaluated using the Eco-Scale Assessment (ESA), Green Analytical Procedure Index (GAPI), and Analytical Greenness Metric (AGREE) metrics, all of which confirmed its environmentally sustainable profile.</p>