This work describes for the first time a stability-indicating HPLC-Corona CAD method for content determination of Artesunate (AS) and Mefloquine hydrochloride (MQ) in coated tablets 100 + 220 mg (ASMQ) developed by Farmanguinhos-Fiocruz. The chromatographic separation was carried out on two Promosil C18 columns in sequence. Chromatography was done using 0.05% formic acid/acetonitrile (80:20) in gradient at flow rate of 1 mL min−1, flow 0.6 mL/min for the right pump, and 0.3 mL/min for the left pump (acetonitrile 100%). The temperature was set at 25 °C for the oven and the detection. The elution time of AS and MQ was found to be 40.5 ± 0.5 min and 10.5 ± 0.5, respectively. The method was validated for system suitability, selectivity, linearity, precision, accuracy, and robustness. The forced degradation studies indicated that AS instability is the major trigger for product degradation, especially under heat and oxidative conditions. In conclusion, the method validation was in agreement with ICH guideline Q2(R1) and AOAC acceptance criteria. Our findings prospected the Corona-CAD detector as a quality control solution regarding the challenges of stability-indicating methods for fixed-dose products.