There is some controversy regarding the interactions between creatine (CRE) and caffeine (CAF) supplements. The aim of this systematic review was to study whether such ergogenic interaction occurs and to analyze the protocol to optimize their synchronous use. The PubMed, Web of Science, MEDLINE, CINAHL, and SPORTDiscus databases were searched until November 2021 following the PRISMA guidelines. Ten studies were included. Three studies observed that CRE loading before an acute dose of CAF before exercise did not interfere in the beneficial effect of CAF, whereas one study reported that only an acute supplementation (SUP) of CAF was beneficial but not the acute SUP of both. When chronic SUP with CRE + CAF was used, two studies reported that CAF interfered in the beneficial effect of CRE, whereas three studies did not report interaction between concurrent SUP, and one study reported synergy. Possible mechanisms of interaction are opposite effects on relaxation time and gastrointestinal distress derived from concurrent SUP. CRE loading does not seem to interfere in the acute effect of CAF. However, chronic SUP of CAF during CRE loading could interfere in the beneficial effect of CRE.