Nasal irrigation is crucial following endoscopic sinus surgery (ESS), especially for managing chronic rhinosinusitis (CRS). This study assessed the effectiveness of N-acetylcysteine (NAC) irrigation during the post-ESS period of patients with CRS without nasal polyposis. In this prospective, single-blind randomized controlled trial, 49 patients (NAC, n = 24; saline, n = 25) undergoing ESS were assigned to receive either NAC or saline irrigations twice daily for a month. The preoperative and postoperative assessments conducted included Lund–Macka (LM) and Lund–Kennedy (LK) endoscopic scores, the Nasal Obstruction Symptom Evaluation (NOSE) scale, and the Sino-Nasal Outcome Test-20 (SNOT-20). At 2 weeks, 1 month, and 3 months after the operation, endoscopic findings and symptoms were evaluated. Both groups showed no differences in age, sex, LM and LK scores, NOSE scale, and SNOT-20 preoperatively. In terms of the endoscopic findings regarding the sinonasal mucosa after ESS, the NAC group had slightly lower scores 2 weeks, 1 month, and 3 months after the operation, but this difference was not statistically significant. The NAC group showed significant improvement in VAS scores, namely, postnasal drip (1.0, p = 0.041), smell dysfunction (0.8, p = 0.003), and crust (1.5, p = 0.034), compared to the control group’s scores of 2.6, 4.7, and 3.6, respectively, 2 weeks after the operation, although no significant differences were observed in VAS scores for any symptoms 1 and 3 months after the operation. NAC was well tolerated, and no adverse events were reported. NAC irrigation showed benefits over saline irrigation in terms of improving postnasal drip, smell dysfunction, and crust after ESS for CRS without nasal polyposis in the immediate postoperative period.