The aim of the study was to evaluate the anti-inflammatory activities of C. gynandra leaf extract cream using an in vivo arachidonic acid-induced ear edema in the rat model. The expression of genes related to rat ear inflammation was measured to evaluate the topical anti-inflammatory activity of C. gynandra cream. The toxicity effect of C. gynandra cream was determined through a skin irritation test in rats and human cumulative skin irritation assessment. Data collected evidently showed a significantly higher percentage of recovery rate in rats treated with C. gynandra cream when compared to the negative control and basal cream (55.8±4.61%), indicating that C. gynandra cream effectively reduced inflammation symptoms in rat ear edema model study. The expressions of all pro-inflammatory cytokines and acute inflammatory-related genes were significantly down-regulated in C. gynandra cream-treated group than untreated group . The dermatological safety aspect of C. gynandra cream was confirmed by human cumulative skin irritation assessment with the average cumulative irritation index of 0.046, indicating a non-irritating effect. The overall findings demonstrated that C. gynandra cream has great potential to be applied for treating skin-related inflammatory diseases.