• Patients must have histologically confirmed DLBCL, irrespective of cell-of-origin. Patients with previously diagnosed indolent lymphoma (follicular lymphoma and marginal zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are eligible only if they have not previously been treated for indolent lymphoma except for local radiation for early-stage disease

• Patients may have received brief treatment with glucocorticoids (up to 250 mg/day prednisone or equivalent for a maximum of 10 days) and/or 1 cycle of chemotherapy such as R-CHOP (or some component\[s\] thereof) for the diagnosis of B-cell lymphoma provided they had staging computed tomography (CT) and/or positron emission tomography (PET)/CT scans prior to glucocorticoids and/or chemotherapy. Treatment must occur within 28 days prior to enrollment

• Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of zanubrutinib in combination with R-CHOP in patients \<18 years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2. Performance status of 3 will be accepted if the impairment is caused by DLBCL complications and improvement is expected once therapy is initiated

• Measurable disease (defined as \>= 1.5cm in diameter) or at least one PET fludeoxyglucose F-18 (FDG) avid area of disease

• Patients must have adequate hematologic, hepatic, and renal function as defined below:

• Hemoglobin \>= 7.0 g/dL

• Absolute neutrophil count (ANC) \> 1,000/mcL

• Platelet count \> 75,000/mcL

• Total bilirubin =\< 1.5 x the upper limit of the normal range (ULN) (unless due to Gilbert's disease)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) \< 2.5 x institutional ULN

• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) \< 2.5 x institutional ULN

• Creatinine clearance \> 40 mL/min calculated by Cockcroft-Gault

• Adequate cardiac function with a left ventricular ejection fraction (LVEF) \>= 50% as assessed by echocardiogram or MUGA (Multigated acquisition scan)

• The effects of zanubrutinib on the developing human fetus are unknown. For this reason and because chemotherapeutic agents used in this study are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 2 weeks prior to initiation of treatment, for the duration of study participation and for 3 months after completing treatment. Should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately. Men must agree to refrain from sperm donation for at least 90 days after the last dose of zanubrutinib

• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[beta-hCG\]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study

• Patients must have the ability to understand and the willingness to sign a written informed consent document and Health Insurance Portability and Accountability Act (HIPAA) consent document. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

• International Prognostic Index must be documented:

‣ ECOG performance status \>= 2 (1 point)

⁃ Age \>= 60 (1 point)

⁃ \>= 2 extranodal sites (1 point)

⁃ Lactate dehydrogenase measurement (LDH) \> upper limit of normal (1 point)

⁃ Ann Arbor Stage III or IV (1 point)

⁃ Is there evidence of transformation from indolent lymphoma?