This phase 2 study evaluated the efficacy and safety of combining acalabrutinib and lenalidomide with either rituximab (ALR) or obinutuzumab (ALO), with longitudinal minimal residual disease (MRD) monitoring in frontline MCL treatment. The primary objective was molecular complete response (CR) after 12 cycles of induction, defined by Lugano criteria, and undetectable MRD of <10-6 (uMRD6) by clonoSEQ. Secondary objectives included safety, responses, and survival. Exploratory objectives included tumor mutation profiles and cell-free DNA (cfDNA) by cancer personalized profiling by deep sequencing. Patients in uMRD6 molecular CR were eligible for discontinuation of acalabrutinib plus lenalidomide after 24 cycles; all patients received a minimum of 36 cycles of anti-CD20 antibody treatment. In the ALR cohort, grade 3/4 hematologic toxicities included neutropenia (38%), thrombocytopenia (4%), and anemia (4%). Nonhematologic toxicities included rash (42%), fatigue (4%), nausea (4%), and vomiting (4%). The overall response rate (ORR) was 100%, CR rate was 83%, and molecular CR rate was 67% after 12 cycles of induction, with best molecular CR at 83%. At a median follow-up of 53 months (range, 46-60), the 4-year overall survival (OS) and progression-free survival (PFS) for ALR were 91% and 76%, respectively. TP53 mutations were adversely associated with PFS (P = .026). For ALO, ORR, CR, and molecular CR were 90% after induction, and 2-year OS and PFS were both at 100%. Longitudinal cfDNA analysis in ALR revealed clonal evolution during response and progression. This safe and active regimen is feasible as a time-limited initial therapy for patients with MCL and warrants further evaluation in response-adapted strategy. This trial was registered at www.ClinicalTrials.gov as NCT03863184.