Abstract Although topical agents have been used to treat cutaneous lupus erythematosus (CLE), there was previously no high-quality evidence of which agents were most effective and which clinical scores were most suitable. On 22 December 2023, a search was conducted across five databases to identify randomized controlled trials (RCTs) for CLE. Two authors independently screened the titles and abstracts of articles based on predetermined criteria. Selected articles were then assessed for inclusion in a blinded manner, with any disagreements resolved through consensus. Data were abstracted in duplicate, and a random-effects model was utilized for network meta-analysis. The certainty of the evidence was evaluated according to the PRISMA guidelines, using the GRADE approach. The analysis was finalized in January 2024, with the primary outcome focused on the change in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) from baseline. Seven RCTs involving 231 participants were analysed. The network meta-analysis revealed that nicotinamide 4% demonstrated the highest probability of achieving the intended outcomes, with a mean difference (MD) of 3.10 and a 95% confidence interval (CI) of 1.99–4.21. Additionally, clobetasol 0.05%, nicotinamide 2% and tacrolimus 0.1% also exhibited statistically significant differences, with MDs of 2.30 (95% CI of 0.73–3.88), 2.30 (95% CI 0.97–3.63) and 1.30 (95% CI 0.03–2.57), respectively. This NMA demonstrates with a high level of evidence that nicotinamide 4%, clobetasol 0.05%, nicotinamide 2% and tacrolimus 0.1% are statistically significant topical agents for CLE. CLASI may be an appropriate outcome to evaluate drug efficacy in CLE.