In this investigation, zirconium oxide (ZrO2) based activation of persulfate (PS) under microwave (MW) irradiation for methyl orange (MO) dye degradation was studied. ZrO2 was synthesized using facile hydrothermal method and it was characterized via XRD, FTIR, SEM, and TGA techniques. Subsequently, MW/ZrO2/PS experiments were conducted to explore the effect of ZrO2 dosage (0–1.5 g/L), initial MO concentration (15–250 mg/L), MW reactor temperature (60–90 ℃), MW power (240–700 W), PS dosage (50–250 mg/L), and presence of NaCl (0–5000 mg/L) on MO removal at pH ~ 7. Under the optimal conditions (ZrO2 ~ 0.5 g/L, MO concentration ~ 25 mg/L, MW temperature ~ 90 ℃, MW power ~ 560 W, and PS dose~250 mg/L), 99 % of MO removal and 85.9 % of TOC removal were observed. Moreover, the toxicity of the initial sample was reduced by 72.9 %. Interestingly, the catalytic oxidation of MO was not affected due to the presence of NaCl. Radical studies confirmed that SO4−⦁ radical was the major active species responsible for MO degradation. Subsequently, the central composite design (CCD) approach was used to find out the interaction effects between MO concentration (10–250 mg/L), PS dosage (50–500 mg/L), and MW treatment time (5–20 min) on MO removal. The CCD based response surface model was found to be significant and reliable (p < 0.0001). Moreover, the chemical cost and energy cost for MW/ZrO2/PS experiments under optimized condition was estimated as $22.5 and $30.3 per kg of MO removal. Overall, transition metal-based PS activation under MW irradiation could be one of the potential alternatives for dye wastewater treatment.