Vitamin C, also known as ascorbic acid, has sparked controversy since it first emerged as a potential anti-cancer agent. However, an increasing number of preclinical studies have demonstrated that high-dose vitamin C exhibits selective anti-tumor effects, including “pro-oxidative cytotoxicity”, “anti-cancer epigenetic regulation”, and “immune modulation”. Consequently, vitamin C has reemerged as a promising anti-cancer therapy in the form of high-dose administration. Advancements in pharmacokinetic research have facilitated the development of clinical trials. Early clinical studies across various cancer types have confirmed the safety of high-dose vitamin C administered via intravenous injection. Moreover, its use as an adjuvant therapy in combination with standard treatments, such as chemotherapy and radiotherapy, has shown promising therapeutic potential. However, there remains a lack of consensus regarding optimal dosage, administration methods, tumor specificity, and patient selection. These factors have contributed to the inconsistent outcomes observed in phase II clinical trials and have hindered the widespread conduct of phase III trials. Without robust clinical evidence, high-dose vitamin C, despite being a non-toxic and promising anti-cancer agent, risks being “shelved” once again. In this review, we provide a comprehensive overview of the anti-tumor mechanisms of high-dose vitamin C and a detailed analysis of preclinical and clinical studies investigating its role as an anti-cancer agent. Additionally, we explore emerging trends in high-dose vitamin C therapy for cancer treatment and offer recommendations for future research in this field.