A salt-induced homogeneous liquid–liquid microextraction (SI-HLLME) protocol combined with high-performance liquid chromatography–diode array detection is presented for the first time for the determination of piroxicam and meloxicam in human urine. The main parameters affecting the performance of the sample preparation protocol were optimized by means of a two-step experimental design (i.e., 2-level fractional factorial design and Box–Behnken design). Following its optimization, the proposed method was thoroughly validated in terms of the total error concept in order to take into consideration the random and systematic errors. For the target analytes, accuracy profiles were constructed, and they were used as graphical decision-making tools. In all cases, the β-expectation tolerance intervals complied with the acceptance criteria of ±15%, proving that 95% of future results will fall within the defined bias limits. The limits of detection were 0.02 μg mL−1 and 0.03 μg mL−1 for piroxicam and meloxicam, respectively. The relative standard deviations were lower than 4.4% in all cases, and the mean relative biases ranged between −5.7 and 3.4% for both drugs. The proposed scheme is simple and rapid, while it is characterized by high sample throughput. Moreover, SI-HLLME requires reduced sample and reagent consumption, according to the requirements of Green Analytical Chemistry.