Purpose: Antibiotic treatment of uncomplicated cellulitis is highly variable with respect to agent, dose, and route of administration. As there is uncertainty about optimal/appropriate time to reassess, we aimed to assess time to clinical response. Methods: We conducted a systematic review of randomized controlled trials reporting clinical response of uncomplicated cellulitis to antibiotic treatment over multiple timepoints. PubMed, Embase, CENTRAL, WHO ICTRP, and clinicaltrials.gov were searched from inception to June 2021 without language restrictions. The primary outcome was time to clinical response. Other outcomes were components of clinical response (pain, severity score, redness, edema measured at ≥ 2 timepoints) and the proportion of patients with treatment failure. We performed a pooled estimate of the average time to clinical response together with 95% confidence intervals using a random effects model. Results: We included 32 randomized controlled trials (n = 13,576 participants). The mean time to clinical response was 1.68 days (95%CI 1.48–1.88; I2 = 76%). The response to treatment for specific components was as follows: ~ 50% reduction of pain and severity score by day 5, a ~ 33% reduction in area of redness by day 2–3, and a 30–50% reduction of proportion of patients with edema by day 2–4. Treatment failure was variably defined with an overall failure rate of 12% (95%CI 9–16%). Conclusion: The best available data suggest the optimal time to clinical reassessment is between 2 and 4 days, but this must be interpreted with caution due to considerable heterogeneity and small number of included studies.