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Utilising tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group (ALLG) translational study sought to characterise primary and acquired molecular determinants of response and resistance of MZL to zanubrutinib for patients treated on the MAGNOLIA clinical trial. WES was performed on baseline tumor samples obtained from 18 patients. For seven patients, ctDNA was interrogated using a bespoke hybrid-capture next-generation sequencing (NGS) assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher's exact test and Kaplan-Meier (log-rank) method respectively. Baseline WES identified mutations in 33/48 (69%) prioritised genes. NFkB, NOTCH or BCR pathway genes were implicated in samples for 16/18 (89%) patients. KMT2D mutations (n=11) were most common followed by FAT1 (n=9), NOTCH1, NOTCH2, TNFAIP3 (n=5) and MYD88 (n=4). MYD88 or TNFAIP3 mutations correlated with improved PFS (not reached (NR) vs 11.1 months, p: 0.008, HR: 0.09, 95% CI: 0.01-0.52); KMT2D mutations trended to worse PFS (PFS: 13.40 months vs NR, p: 0.05, HR 6.5, 95%CI: 1.00-37.78). Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in two patients whose disease progressed. A BTK E41K non-catalytic activating mutation was identified prior to treatment in one zanubrutinib-refractory patient. MYD88, TNFAIP3 and KMT2D mutations correlate with PFS in patients with rrMZL treated with zanubrutinib. Detection of acquired BTK and PLCG2 mutations in ctDNA while on therapy is feasible and may herald clinical disease progression. This trial was registered at https://anzctr.org.au/ as ACTRN12619000024145.