Objective To investigate the expression and clinical significance of methyltransferase like 3 (METTL3) and Wilms' tumor 1⁃associating protein (WTAP) in patients with diffuse large B⁃cell lymphoma (DLBCL). Methods A total of 84 newly diagnosed DLBCL patients were selected as the DLBCL group, and 50 patients with reactive lymph node hyperplasia (RLH) as the RLH group. Expressions of METTL3 and WTAP were compared between patients of the two groups, and between DLBCL patients with different clinical characteristics. The correlation between METTL3 expression and WTAP expression was analyzed in DLBCL patients. The short⁃term chemotherapy efficacy was compared between DLBCL patients with different expressions of METTL3 and WTAP. The Kaplan⁃Meier curve was drawn to analyze the relation of METTL3 and WTAP expressions with prognosis of DLBCL patients. The COX proportional risk model was adopted to analyze the factors for affecting prognosis of DLBCL patients. Results The positive rates of METTL3 and WTAP were higher in the DLBCL group than in the RLH group (P<0.05). METTL3 expression positively correlated with WTAP expression in DLBCL patients (P<0.05). DLBCL patients with Ann Arbor clinical staging in Ⅲ-Ⅳ, Hans classification in non⁃GCB type obtained higher positive rates of METTL3 and WTAP as compared with DLBCL patients with Ann Arbor clinical staging in Ⅰ-Ⅱ, Hans classification in GCB type (P<0.05). The objective remission rate and 3⁃year survival rate of patients with METTL3 and WTAP positive were lower as compared with patients with METTL3 and WTAP negative, respectively (P<0.05). Ann Arbor clinical staging in Ⅲ-Ⅳ, METTL3 positive, WTAP positive were the risk factors for affecting the prognosis of DLBCL patients (P<0.05). Conclusion Expressions of METTL3 and WTAP are elevated in DLBCL patients, their expressions are related to Ann Arbor clinical staging and Hans classification of DLBCL patients. Patients with high METTL3 and WTAP expressions obtain a relatively low 3⁃year survival rate, and both two as above are the influencing factors for DLBCL prognosis.