Aims: This review aims to evaluate prospective controlled trials of primary prevention of anthracycline cardiotoxicity in paediatric cancer patients. Methods and Results: Prospective controlled trials in which any cardioprotective agent was compared to no additional therapy or placebo in paediatric cancer patients receiving anthracyclines (PROSPERO: CRD42022367791). Outcomes were assessed using random and fixed-effects meta-analysis models as well as a synthesis without meta-analysis approach. A total of 24 reports of 19 trials were included in our review, 11 trials administered dexrazoxane, two trials administered the angiotensin converting enzyme inhibitor enalapril, one trial administered the beta-blocker carvedilol, one omega-3 fatty acids, one coenzyme Q10, one amifostine, one silymarin and one black seed oil. A total of 1333 paediatric patients receiving anthracyclines were included in meta-analysis of the cardio-protective effect of dexrazoxane in reducing the risk of developing significant systolic dysfunction. A risk ratio of 0.44 (95% CI: 0.33 to 0.61; I2 = 0%) was found, showing that the administration of dexrazoxane was highly effective. Overall, enalapril, carvedilol and dexrazoxane resulted in less left ventricular dysfunction and fewer cardiac biomarker abnormalities compared to placebo. Omega-3 fatty acids, silymarin and black seed oil each demonstrated benefit through less reduction of systolic function and fewer cardiac biomarker abnormalities. Conclusion: Enalapril and dexrazoxane are highly effective in preventing the anthracycline-induced cardiotoxicity in paediatric cancer patients with a highly acceptable safety profile. More randomised-controlled trials are required to reach a conclusion on the efficacy of omega-3 fatty acids, co-enzyme Q10 and amifostine.