In this research, sponge‐activated carbon was applied as an effective adsorbent for simultaneous dispersive solid ultrasound‐assisted microextraction followed by high‐performance liquid chromatography for the preconcentration and determination of losartan (LOS) and chlordiazepoxide (CDP) drugs from urine and plasma samples. The synthesized adsorbent was characterized using scanning electron microscopy and Brunauer–Emmett–Teller techniques. To investigate the effects of different parameters, such as adsorbent dosage, pH, adsorption time, and volume of extraction solvent on the extraction process of LOS and CDP, a central composite design (CCD)‐based response surface methodology was applied. Using a CCD, the optimized factors achieved an adsorption time of 13 min, an adsorbent dosage of 14 mg, an extraction solvent (methanol) of 1.3 mL, and pH = 4.7 under the desirability function. Under the optimized conditions, the presented method showed a wide linear range of 0.005–10.0 μg/mL with a limit of detections of 0.0011 and 0.0018 μg/mL for LOS and CDP, respectively. Moreover, the applied method had relative standard deviations of 4.7% and 5.3% for LOS and CDP, respectively.