Hyperprolactinemia (hPRL) often poses a diagnostic dilemma due to the presence of macroprolactin. Understanding the prevalence of macroprolactinemia (mPRL) has an important implication in managing patients with hPRL. The primary aim of this study was to determine the prevalence of mPRL globally and to explore selected factors influencing the prevalence estimate. Studies with original data related to the prevalence of mPRL among patients with hPRL from inception to March 2020 were identified, and a random effects meta-analysis was performed. Of the 3770 records identified, 67 eligible studies from 27 countries were included. The overall global prevalence estimate was 18.9% (95% CI: 15.8%, 22.1%) with a substantial statistical heterogeneity (I2 = 95.7%). The highest random effects pooled prevalence was observed in the African region (30.3%), followed by Region of the Americas (29.1%), European (17.5%), Eastern Mediterranean (13.9%), South-East Asian (12.7%), and Western Pacific Region (12.6%). Lower prevalence was observed in studies involving both sexes as compared to studies involving only female participants (17.1% vs. 25.4%) and in more recent studies (16.4%, 20.4%, and 26.5% in studies conducted after 2009, between 2000 and 2009, and before 2000, respectively). The prevalence estimate does not vary according to the age group of study participants, sample size, and types of polyethylene glycol (PEG) used for detection of macroprolactin (PEG 6000 or PEG 8000). With macroprolactin causing nearly one-fifth of hPRL cases, screening for mPRL should be made a routine before an investigation of other causes of hPRL.