Topical occlusive agents, such as petroleum jelly and silicone oils, kill head lice by coating and blocking its excretory system and are unlikely to induce treatment resistance. Although a popular alternative to neurotoxic pediculicides, their efficacy and safety remain unclear. We searched CENTRAL, MEDLINE, HERDIN (from inception to October 31, 2017), and other relevant sources for randomized controlled trials that compared topical occlusive agents with neurotoxic pediculicides to treat patients with head lice infestation. Using Cochrane collaboration methods, we selected studies, assessed risk of bias, and pooled similar studies. We assessed certainty of evidence using GRADEPro. Seventeen trials (N = 2005) testing occlusive agents met inclusion criteria. Risk of bias was moderate across trials, mainly from lack of blinding of participants and personnel. As a class, occlusive agents may be more pediculicidal than neurotoxic agents (final cure rate, RR 1.20, 95% CI 1.02, 1.41; 16 RCTs, N = 1779; I2 = 88%; low certainty of evidence). Post hoc subgroup analysis suggests that this benefit may be limited to synthetic combination occlusive products. Adverse effects, such as skin and eye irritation, are similar between groups (RR 0.65, 95% CI 0.36, 1.17; 15 RCTs, N = 1790; I2 = 28%; low certainty of evidence). In treating head louse infestation, evidence suggests occlusive agents may be superior to or equally efficacious as neurotoxic pediculicides. Adverse effects are few and minor. Future trials should use appropriate comparators and consider effects of confounders such as neurotoxin resistance. Additionally, optimal occlusive formulation and dosing regimen need to be determined.