Abstract Introduction Oral mucositis (OM) is a major side effect of cancer therapy, which is associated with significant symptoms, treatment delays and increased costs for the health system. It is an important component of the quality of life of cancer patients and, until now, there has been no gold standard regarding prevention or treatment of this pathology. Notwithstanding the paucity of treatment guidelines (due to limited evidence from high-quality, rigorous studies), sodium bicarbonate (SB) rinses are one of the most used agents for OM management. Objectives A systematic review (2000–2022) was performed in order to compare and examine different agents versus sodium bicarbonate (SB) in preventing or treating OM. Sources Eleven randomized controlled trials (RCT) were evaluated: four were conducted for the prevention and seven for the management of OM. The risk of bias of RCTs was assessed using the revised Cochrane risk of bias tool for randomized trials. Study selection According to the RoB2 evaluation for randomized trials, four RCTs were judged to be at a high risk of bias, two were rated as ‘problematic’, while five were deemed to be a low risk of bias. Conclusions The results revealed that there was no evidence for supporting SB in OM treatment regarding management and prevention. Clinical significance Results showed in this review takes on a strategic importance in the use of SB for OM management or prevention; indiscriminate use of SB could be counterproductive because it causes a sudden pH increase and it delays proper OM pharmacological treatment.