<p>The utilization of microwave-assisted extraction represents a pioneering approach for obtaining crocins from saffron stigmas with high contents. The primary aim of this research is to explore this innovative extraction technique. To achieve this goal, we employed a three-factorial Box-Behnken design (BBD) to optimize key extraction parameters, namely extraction time (2–14 min), solid-to-solvent ratio (4–10 mg/40 mL), and microwave power (100–700 W). The experimental data based on analysis of variance and multiple regression method were used to ensure the fitness and competence of the models. The maximum content of crocins with the highest antioxidant activity and coloring power was reached at the optimal settings of 9.23 min as extraction time with 7.41 mg/40 mL solid-to-solvent ratio at 400 W of applied microwave power. The accuracy of the RSM predictive models was validated using optimal conditions of crocin microwave-assisted extraction. At these optimum conditions, HPLC analysis revealed nine dominant crocetin esters, picrocrocin, and safranal in saffron extract. Additionally, two flavonol O-glycosides were detected (kaempferol-3-sophoroside-7-glucoside and kaempferol-3-sophoroside). This research provides new insights into the combined effects of key parameters in microwave-assisted extraction of crocins, paving the way for their application as natural colorants and antioxidants in food industry.</p>