This study pooled the clinical outcomes of 18 high-quality studies managing MGD with azithromycin. Symptom score was the primary and clinical signs were the secondary outcome measures. Overall effectiveness of topical azithromycin (TA) and oral azithromycin (OA) was measured by standard mean difference (SMD). Additionally, outcomes of TA vs. oral doxycycline (OD) were compared. The overall pooled symptom scores were significantly reduced after administering both TA and OA [P<0.0001; SMD=1.54 (95% CI: 1.15-1.92)]. Similarly, the combined eyelid signs, plugging of the meibomian gland, meibum quality and tear secretion were distinctly improved. However, significant improvements for tear breakup time (TBUT) and corneal staining were achieved by TA but not OA. Improvements in primary and secondary outcomes were not statistically different between TA and OD. Pooled adverse event rates for TA were 25%, and limited to ocular discomfort, redness and blurred vision. Adverse event rates for OA were 7%; limited to gastrointestinal upset and decreased appetite. The absence of systemic adverse events suggests TA may be safer and more suitable for children and child-bearing women. The effectiveness of treating MGD with either TA or OA was basically confirmed. TA is superior over OA or OD in improving tear film quality, particularly in the short term.