Background <p>Oral mucositis (OM) is a frequent and debilitating complication in patients undergoing chemotherapy for hematologic malignancies, significantly impacting quality of life and treatment outcomes. Despite its clinical importance, limited consensus exists regarding the most effective topical treatments for preventing and managing chemotherapy-induced OM. This retrospective study aimed to compare the efficacy of three commonly used mouthwash agents: benzydamine hydrochloride, sodium bicarbonate (NaHCO₃), and Ankaferd hemostat in preventing and treating chemotherapy-induced OM in patients with hematologic malignancies, and to identify clinical and laboratory factors associated with OM development.</p> Methods <p>Medical records of 82 patients with hematologic malignancies who received chemotherapy and prophylactic mouthwash treatment between January 2018 and December 2020 were retrospectively analyzed. Patients were retrospectively classified according to the mouthwash agent administered by the treating clinicians: benzydamine hydrochloride, sodium bicarbonate, or Ankaferd hemostat. Oral mucositis severity was assessed using the World Health Organization (WHO) grading scale at baseline and weekly for three consecutive weeks. Laboratory parameters, including complete blood count and biochemical markers, were also evaluated. Statistical analysis included chi-square tests, Fisher’s exact test, and logistic regression to identify factors associated with OM development.</p> Results <p>At the third week of follow-up, patients using benzydamine hydrochloride and Ankaferd hemostat demonstrated significantly lower rates of oral mucositis compared to those using sodium bicarbonate (<i>p</i> &lt; 0.05). Specifically, benzydamine hydrochloride and Ankaferd hemostat were associated with reduced OM incidence, whereas sodium bicarbonate use correlated with higher OM rates. Additionally, higher platelet counts were independently associated with reduced risk of developing oral mucositis. No significant differences were observed in other hematologic or biochemical parameters among the three treatment groups.</p> Conclusions <p>Benzydamine hydrochloride and Ankaferd hemostat appear to provide superior local mucosal protection compared to sodium bicarbonate in preventing and treating chemotherapy-induced oral mucositis in patients with hematologic malignancies. These findings suggest that the choice of prophylactic mouthwash may significantly influence OM outcomes and highlight the potential for optimizing supportive care strategies in this vulnerable patient population. Further prospective, randomized controlled trials are warranted to confirm these findings and establish evidence-based guidelines for OM prevention and management.</p>