Objective: An optimized quick, easy, cheap, effective, rugged, and safe (QuEChERS) technique was investigated and compared with the conventional QuEChERS technique for the simultaneous analysis of fifty-three pesticide residues in safflower using ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). Method: Graphitic carbon nitride (g-C3N4) consisting of a major amount of carbon and nitrogen with a large surface area was used as a QuEChERS adsorbent instead of graphitized carbon black (GCB) for safflower extraction purification. Validation experiments were performed using spiked pesticide samples, and real samples were analyzed. Results: The linearity of the modified QuEChERS technique was evaluated with high coefficients of determination (R-2) being higher than 0.99. The limits of detection were <10 μg/kg. The spiked recoveries ranged from 70.4% to 97.6% with a relative standard deviation of less than 10.0%. The fifty-three pesticides exhibited negligible matrix effects (<20%). Thiamethoxam, acetamiprid, metolachlor, and difenoconazole were detected in real samples using an established method. Conclusion: This work provides a new g-C3N4-based modified QuEChERS technique for multi-pesticide residue analysis in complex food matrices.