Background: Oral mucositis (OM) is an inflammation affecting the oral mucosa. It is characterized by erythema, ulcers, edema, and is frequently seen in patients undergoing cancer treatment. Therefore, it’s one of the main complications of cancer patients receiving therapy. OM can be a dose-limiting condition that complicates cancer treatment and can even decrease chances of survival. Methods: Studies up to June 2020 were searched through databases including Embase, MEDLINE, and CENTRAL. The primary outcome was the incidence of oral mucositis for the trials employing oral cryotherapy (OC) as the intervention for prevention of OM and reduction in the severity of OM for the trials employing low-level laser therapy (LLLT) for the treatment of OM. Secondary outcomes were the duration of hospitalization, pain scores, need for analgesics, and OM duration. A systematic review with a meta-analysis of randomized controlled trials (RCTs) was performed using the random-effects model. Random errors of the meta-analyses were detected by performing Trial Sequential Analysis (TSA). Results: A total of 14 RCTs with 805 participants were included in the present meta-analysis for the trials employing OC as the intervention for the prevention of oral mucositis. OC was associated with a significantly lower risk of oral mucositis (relative risk (RR), 0.67 (95% CI: 0.56‐ 0.81, p<0.05). Very high heterogeneity was identified between the studies (I2 = 90 %). Results of the subgroup analysis further showed that oral cryotherapy significantly reduced OM in patients undergoing bone marrow transplantation (BMT) (RR 0.69, CI: 0.54-0.89, p<0.05) as well as chemotherapy (RR-0.66, CI: 0.58-0.75, p<0.05). The heterogeneity was null among the trials with chemotherapy. Findings from Trial Sequential Analaysis suggested that the evidence for the reduction in risk of developing OM with cryotherapy employed as a preventive intervention was conclusive. For LLLT, a total of 6 RCTs with 200 participants were included. LLLT significantly decreased the risk of severe OM when compared to placebo or no therapy (RR 0.43, 95% CI 0.20 to 0.93; p<0.0 5). High heterogeneity was identified (I2= 80.3%). The funnel plot indicated publication bias. The same effect was demonstrated on the efficacy of LLLT by the sensitivity analysis with a RR of 0.28 (95% CI 0.16 to 0.48); however, heterogeneity was reduced to 0% depicting high-quality evidence. Trial Sequential Analaysis reinforced the conclusiveness of this evidence. Conclusion: The result of the meta-analyses illustrates a significant benefit from OC in preventing and low-level laser therapy in the treatment of OM in patients undergoing cancer treatment. Keywords: oral mucositis, oral cryotherapy, low-level laser therapy, systematic review, meta-analysis, trial sequential analysis