Background <p>Achieving adequate pain control during vital pulp therapy in children with molar-incisor hypo-mineralization (MIH) is challenging because of hypersensitivity and the difficulty of obtaining profound local anesthesia. This study evaluated the effect of ibuprofen premedication on intraoperative pain during vital pulp therapy in MIH-affected mandibular first permanent molars in children.</p> Methods <p>This triple-blind randomized clinical trial was conducted on 32 children aged 6–9 years with MIH requiring vital pulp therapy. Participants were randomly assigned to receive either ibuprofen suspension (10 mg/kg) or placebo 45 min before treatment. Pain intensity was assessed using the Five-Face Visual Analog Scale (VAS) at pulp entry and the Sound-Eye-Motor (SEM) scale during the procedure. Data were analyzed using SPSS version 26, with a significance level of 0.05.</p> Results <p>The mean age of participants was 7.99 ± 0.59 years in the ibuprofen group and 8.01 ± 0.46 years in the placebo group. Intraoperative pain scores were significantly lower in the ibuprofen group compared with the placebo group according to both VAS (<i>p</i> = 0.004) and SEM scores (<i>p</i> = 0.001).</p> Conclusions <p>Premedication with ibuprofen significantly reduced intraoperative pain during vital pulp therapy in MIH-affected mandibular first permanent molars in children aged 6–9 years.</p> Trial registration <p>Iranian Registry of Clinical Trials (IRCT), IRCT20250308064976N1. Registered on 22 April 2025.</p>