The time until a patient achieves a relevant improvement during the treatment of a skin disease is important for selecting a therapy, but has been largely neglected in reviews and guidelines. The aim of this systematic review was to determine the time until the onset of action (TOA) of topical acne treatments. The primary outcome was the TOA defined as the time until a 25% reduction in the mean number of inflammatory lesions had been achieved. A systematic literature search in Medline and Embase was carried out. Clinical trials that evaluated head-to-head comparisons of treatments in patients suffering from mild-to-moderate papulopustular acne were included. Abstract and full-text screening and data extraction were done independently by two investigators. With respect to inflammatory lesions, different concentrations of benzoyl peroxide (BPO) or adapalene did not seem to influence the TOA. BPO seemed to act more quickly than isotretinoin and tretinoin. Adapalene showed a shorter TOA than isotretinoin. Conflicting results were seen when comparing adapalene with tretinoin, with a tendency for adapalene to be faster. Clindamycin/BPO seemed to act more quickly than adapalene. Inconsistent results were seen for the comparison of clindamycin/BPO and BPO alone with a slight indication of a shorter TOA for clindamycin/BPO. Adapalene/BPO and clindamycin/BPO showed comparable TOA. When interpreting the data, the different study designs and the limited study quality need to be taken into account. Further research is needed to identify treatments that offer an early onset of action and possibly help to optimize patients' adherence. TOA should be considered as an additional outcome in acne trials.