Purpose: To evaluate the efficacy and safety of Houttuynia eye drops (a Chinese traditional medicine) atomization treatment in meibomian gland dysfunction (MGD)-related dry eye disease (DED) patients. Methods: A total of 240 eligible patients diagnosed with MGD-related DED were assigned either Houttuynia eye drops or placebo for atomization once daily for four weeks in a multi-center, randomized, double-blind, placebo-controlled clinical study. Primary outcome evaluations used included eye symptom score (using the Chinese Dry Eye Questionnaire), meibum quality, and tear break-up time (TBUT), while safety evaluations included adverse events (AEs), visual acuity, and intraocular pressure monitoring. Indicators were measured at baseline as well as one week, two weeks, and four weeks after treatment. Results: Primary outcome measures of the Houttuynia group were improved compared with their placebo counterparts following four-week treatment. Eye symptom scores were significantly reduced relative to the baseline in the Houttuynia group (mean +/- standard error of the mean, 9.00 +/- 0.61) compared with the placebo group (6.29 +/- 0.55; p = 0.0018). Reduction in meibum quality score in the Houttuynia group (0.91 +/- 0.10) was also significantly higher compared with the placebo group (0.57 +/- 0.10; p = 0.0091), while TBUT in the treatment group (6.30 +/- 0.22) was also longer than in the latter (5.60 +/- 0.24; p = 0.0192). No medication-related adverse events were observed. Conclusions: Atomization treatment with Houttuynia eye drops is both clinically and statistically effective for the treatment of mild to moderate MGD-related DED patients. This approach is generally safe and was tolerated well by patients.