Timing chemotherapy on the basis of the body's intrinsic circadian clock—ie, chronomodulated chemotherapy—might improve efficacy and reduce treatment toxicity. This systematic review summarises the available clinical evidence on the effects of chronomodulated chemotherapy from randomised, controlled trials in adult patients with cancer, published between the date of database inception and June 1, 2021. This study complies with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered on the International Prospective Register of Systematic Reviews (CRD42020177878). The protocol was published on Oct 21, 2020, before study initiation. The primary outcome measures comprised toxicity incidence, overall survival, progression-free survival, and objective response rate. Of 1455 identified abstracts, 18 studies including 2547 patients were selected. Studies were heterogeneous in study design, treatment, and population. 14 (77%) of 18 studies reported differences among groups in toxicity. 11 (61%) studies reported that chronomodulated chemotherapy resulted in a significant decrease in toxicity while maintaining anti-cancer activity. Two (11%) studies showed that chronomodulated chemotherapy reduced some toxic effects but increased others, and one (6%) study reported worse toxicity outcomes than standard chemotherapy. Three (17%) studies reported improved efficacy (survival measures, objective response rate, or time to treatment failure) of chronomodulated chemotherapy, and no studies reported a decrease in efficacy. In conclusion, most studies provide evidence of the reduction of toxicity resulting from chronomodulated chemotherapy, while efficacy is maintained. More and larger, carefully designed, randomised, controlled trials are needed to provide recommendations for clinical practice.