Background: Clinical trials examining the therapeutic benefit of modafinil in MS fatigue provide conflicting data. The goal of this study was to systematically evaluate the efficacy of modafinil using a meta-analytic method. Methods: A systematic literature search was performed on published peer reviewed articles from 2000 to 2017 using the Cochrane Library, PubMed, and EMBASE. This review included double blind, randomized controlled trials, which evaluated modafinil in MS fatigue. The primary outcome measure was the estimated treatment difference in the Modified Fatigue Impact Scale score (MFIS) and Fatigue Severity Scale score (FSS). A secondary outcome measure was the estimated treatment difference in the Symbol Digit Modalities Test (SDMT). Results: A total of 303 patients from five randomized controlled trials were included in the analyses. Modafinil was superior to placebo with an estimated treatment difference according to the MFIS (MD = -5.27, 95% CI: -8.51 to -2.03, P = 0.001). For the FSS, there was no significant difference between the two groups (MD = 2.50, 95% CI: -0.70 to 5.70, P = 0.13). For the secondary outcome, there was no significant difference between groups studied using the SDMT (MD = 0.23, 95% CI: -0.25 to 0.71, P = 0.35). Conclusions: Our meta-analysis showed that modafinil was an effective pharmacologic therapy for MS fatigue. Additional research is required to determine optimal dosing and treatment schedules.