Abstract: Pice quality is often required to monitor the routine pesticide residues. However, there are matrix sensitivity variations during operation. In this study, the UHPLC-MS/MS approach was developed to simultaneously determine the thiodicarb and methomyl in spices (chili, pepper, and spearmint). A systematic optimization of the chromatographic system was undertaken for the optimal separation, sensitivity, and robustness. Sample preparation was commenced with the acetonitrile extraction of the homogenized spice samples, followed by a clean-up step using a modified QuEChERS-based dispersive solid-phase extraction (d-SPE) procedure. Specifically, the materials were also employed as the 50 mg of primary secondary amine (PSA), 10 mg of graphitized carbon black (GCB), and 150 mg of anhydrous magnesium sulfate per 1.5mL of the extract. Three analytical columns with the stationary phases were evaluated after optimization under chromatographic conditions: A BEH C18 column (1.7 μm, 100 mm × 2.1 mm), a BEH HILIC column (1.7 μm, 100 mm × 2.1 mm), and an HSS T3 column (1.8 μm, 100 mm × 2.1 mm). The HSS T3 column was specifically designed to retain the polar compounds, indicating the markedly superior performance, thus providing for the excellent peak shape and sufficient retention for both analytes. Subsequent optimization was focused on the mobile phase composition. Four systems were compared: acetonitrile with 0.05% formic acid in water, methanol with 0.05% formic acid in water, pure acetonitrile with water, and pure methanol with water. The optimal methanol-water system was selected without the acid modification. There was a significant increase in the peak area, approximately 57% higher for the thiodicarb. The methomyl was improved to maintain the excellent peak symmetry, compared with the acidified systems. The flow rate was optimized in a range from 0.15 to 0.55 mL/min. A flow rate of 0.35 mL/min was identified as the ideal compromise, indicating a significant enhancement in the peak area, compared with the higher flow rates. The total time was also maintained. The column temperature was examined from 25°C to 65°C. A temperature of 55°C was found to maximize the detector response for both compounds. The thiodicarb shared a particularly significant 31.4% increase in the peak area, compared with 25°C. The injection volume was 2 μL, as the excessive volume compromised the chromatographic integrity. Mass spectrometric detection was performed using electrospray ionization in the positive mode (ESI+) with multiple reaction monitoring (MRM). The optimal performance was achieved by the effective separation of the thiodicarb and methomyl within 3 min, with the reproducible retention times of 2.68 and 2.10 min, respectively. The slope ratio of the matrix-matched versus solvent-based calibration curves revealed that there was extreme signal enhancement in the significant matrix, particularly for the methomyl in chili (ME = 1815.6%). Matrix-matched calibration was therefore essential for the accurate quantification. There was excellent linearity from 0.001 to 1 mg/L in all spice matrices, with the correlation coefficients (r) ≥ 0.9980. The accuracy and precision were validated after recovery tests at three fortification levels (0.002, 0.01, and 0.5 mg/kg) with five replicates. Mean recoveries ranged from 84.3% to 107.7%, with the CV of 3.0%-8.8%. The high sensitivity was obtained with an LOQ of 0.002 mg/kg and LOD of 0.16 × 10^-3 μg/kg, below the regulatory limits. The optimal, sensitive, and robust UHPLC-MS/MS can be expected to simultaneously quantify the thiodicarb and methomyl in the complex spice matrices. The systematic optimization of the chromatographic system, particularly the selection of the HSS T3 column and the methanol-water mobile phase, effectively mitigated the analytical challenges and detection sensitivity. Its suitability was also verified for the routine application in the regulatory monitoring and quality control laboratories, thereby strengthening the safety of the spices in the global food supply chain.