Purpose of Review The purpose of this meta-analysis is to compare the efficacy, success, and side effects of single-dose and two-dose methotrexate (MTX) protocols, which are two extensively administered medical protocols in ectopic pregnancy (EP) treatment. Recent Findings Two-dose protocol is relatively new proposed protocol, and especially it could be advised to decrease single-dose MTX failure rate, which is 20%. Two-dose protocol resulted in a significantly higher odds of treatment success and lower odds of treatment failure. Summary Totally 8 publications were selected according to the predetermined eligibility criteria. Two-dose protocol was superior to the single-dose protocol in means of achieving treatment success (OR = 1.58; 95% CI, 1.09-2.29; p = 0.016) and length of follow-up (SMD = 1.22; 95% CI, 1.05-1.39; p < 0.001). In other parameters, two-dose protocol is non-inferior to the single-dose application: for the odds of side effects (OR = 1.23; 95% CI, 0.88-1.72; p = 0.226) and surgery for tubal rupture (OR = 0.48; 95% CI, 0.21-1.09; p = 0.079). Treatment with two-dose MTX has more success rate than one dose protocol. It could be postulated that two-dose protocol could be advised to apply the patients when on day 4 of MTX hCG levels not decrease more than usual, as well. Therefore, it could be recommended that the two-dose MTX protocol would be the main protocol in patients with non-surgically managed for EPs.