BACKGROUND: Plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) are frequently associated with substantial pain burden and functional impairment. Mitogen-activated protein kinase kinase (MEK) inhibitors have demonstrated efficacy in tumor control; however, their impact on patient-reported pain outcomes remains incompletely characterized. We conducted a systematic review and meta-analysis to evaluate the effect of MEK inhibitors on pain intensity, pain interference, and clinically meaningful pain improvement in patients with NF1-associated PN. METHODS: A systematic search was conducted to identify clinical trials evaluating MEK inhibitors in NF1-associated PN reporting patient-reported pain outcomes. Continuous outcomes (pain intensity and pain interference) were pooled using random-effects models, and responder outcomes were analyzed using proportion meta-analysis. Standard deviations were derived or estimated when not directly reported. Heterogeneity was assessed using the I² statistic. RESULTS: After screening 359 records, a total of 7 clinical trials comprising 8 analyzable cohorts, and 342 patients were included in the quantitative synthesis on pain intensity. MEK inhibitor therapy was associated with a statistically significant reduction in pain intensity (mean change -1.65; 95% Confidence Interval, -2.20 to -1.10; I² = 71.4%). Seven studies, encompassing 222 patients, were analyzed for pain interference, revealing a modest yet statistically significant enhancement (mean change -0.65; 95% Confidence Interval, -0.94 to -0.36; I² = 32.7%). Responder analysis, including four studies, indicated that 67% of patients achieved a clinically meaningful pain reduction (≥2-point decrease), with low heterogeneity (95% Confidence Interval, 30%-74%; I² = 1.1%). Subgroup analyses demonstrated generally consistent improvements across pediatric and adult cohorts, with no significant subgroup differences. CONCLUSIONS: MEK inhibitor therapy is associated with significant improvements in patient-reported pain outcomes in NF1-associated PN, including reductions in pain intensity and interference, as well as a high proportion of patients achieving clinically meaningful improvement. While the average reduction in pain intensity did not reach the threshold for clinically meaningful change at the population level, responder analyses demonstrate substantial benefit in a significant subset of patients. These findings support the role of MEK inhibitors as a disease-modifying therapy with meaningful symptomatic benefit.