Background Chronomodulated chemotherapy aims to achieve maximum drug safety and efficacy by adjusting the time of treatment to an optimal biological time as determined by the circadian clock. Although it is a promising alternative to conventional (non–time-stipulated) chemotherapy in several instances, the lack of scientific consensus and the increased logistical burden of timed administration limit the use of a chronomodulated administration protocol. Objective With the goal to increase scientific consensus on this subject, we plan to conduct a systematic review of the current literature to compare the drug safety and efficacy of chronomodulated chemotherapy with those of conventional chemotherapy. Methods This systematic review will comply with the PRISMA (Preferred Reporting Items for the Systematic Reviews and Meta-Analysis) guidelines. In order to identify relevant studies, we conducted a comprehensive search in PubMed and Embase on May 18, 2020. We included clinical studies that compare either the safety or efficacy of chronomodulated chemotherapy with that of conventional chemotherapy. Potential studies will be reviewed and screened by 2 independent reviewers. Quality assessment will be performed using the National Institutes of Health’s Study Quality Assessment Tool (Quality Assessment of Controlled Intervention Studies). Disagreements will be resolved by consulting a third independent reviewer. Results This protocol has received funding, and the search for studies from databases commenced on May 18, 2020. The systematic review is planned to be completed by October 31, 2020. Conclusions In this systematic review, we will compare drug safety and drug efficacy for cancer patients who were administered either chronomodulated chemotherapy or conventional chemotherapy. Moreover, we will highlight the outcomes and quality of the selected trials for this review. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42020177878; https://tinyurl.com/y53w9nq6 International Registered Report Identifier (IRRID) PRR1-10.2196/18023