Abstract Background Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β) are among the cytokines released secondary to the surgical stress response. The objective of this study was to investigate the effect of a Transversus Abdominis Plane (TAP) block on postoperative pain and its immunomodulatory activity through proinflammatory cytokines. Methods TAP (study group; n = 40) or p-TAP (placebo group; n = 40). Patients in the TAP group underwent an Ultrasound (US) guided unilateral TAP block using 20-cc 0.5% bupivacaine solution. Patients in the p-TAP group underwent a sham block using 20-cc isotonic solution. The TNF-α and IL-1β levels were measured three times at preoperative hour-0 and postoperative hours 4 and 24. Visual Analog Scale (VAS) scores were recorded at 0-hours, 30-minutes, 4-hours, and 24-hours. Analgesic use within the first 24-hours following surgery was monitored. Results The postoperative VAS score was decreased in the TAP group at all time points (0, 4, and 24 hours), and the differences between groups were statistically significant (p < 0.001 for all comparisons). In the TAP group, the TNF-α and IL-1β levels at 4 and 24 hours post operation were significantly lower than the preoperative levels (p < 0.001 for all comparisons). Conclusion The TAP block for pre-emptive analgesia enabled effective hemodynamic control during the intraoperative period, provided effective pain control in the postoperative period, and decreased inflammation and surgical stress due to the decreased levels of the proinflammatory cytokines TNF-α and IL-1β in the first postoperative 24 hours, indicating immunomodulatory effect.