Obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness (EDS). Pharmacotherapy offers a potential treatment approach for EDS in OSA patients. This systematic review and meta-analysis aimed to assess the efficacy and safety of pharmacological interventions for alleviating EDS in patients with OSA. Following PRISMA guidelines, we included randomized controlled trials investigating pharmacological treatments for EDS in adult OSA until August 2023. We conducted meta-analysis, subgroup, and meta-regression analyses using a random effects model. Finally, a network meta-analysis synthesized direct and indirect evidence, followed by a comprehensive safety analysis. We included 32 articles in the meta-analysis (n = 3357). Pharmacotherapy showed a significant improvement in the Epworth Sleepiness Scale (ESS) score (Mean Difference (MD) −2.73, (95 % Confidence Interval (CI) [−3.25, −2.20], p < 0.01) and Maintenance of Wakefulness Test (MWT) score (MD 6.00 (95 % CI [2.66, 9.33] p < 0.01). Solriamfetol, followed by Pitolisant and modafinil, exhibited the greatest ESS reduction, while Danavorexton, followed by Solriamfetol and MK-7288, had the strongest impact on MWT. MK-7288 had the most total adverse events (AEs), followed by Danavorexton and armodafinil. Pharmacological Interventions significantly alleviate EDS in OSA patients but with heterogeneity across medications. Treatment decisions should involve a personalized assessment of patient factors and desired outcomes.