Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia, particularly in Indonesia. Despite advances in treatment, patients with advanced NPC face poor outcomes. Examining the NPC mutational landscape is crucial for understanding its biology and enable potential new therapeutic strategy. To characterize the landscape of single nucleotide variants (SNVs), structural variants (SVs), copy number variations (CNVs), and short tandem repeats (STRs) in locally advanced to advanced NPC within an Indonesian cohort using long-read sequencing. Six fresh-frozen nasopharyngeal biopsy samples were collected from the NPC biobank. DNA was extracted and sequenced using Oxford Nanopore’s Promethion 2 Solo long-read sequencer. Structural and small variants were identified and annotated. The SNVs, SVs, and CNVs were categorized based on predicted effects, and key findings were validated using external RNA-seq data. Copy number loss genes were checked against the Tumour Suppressor Gene database (TSGene v2.0). Genetic findings were correlated with patient clinical histories. Approximately 4.4 to 5.1 million SNVs were identified per sample, with 0.023% categorized as high consequence. Notable tumour suppressor genes, such as LIMD1 and CNDP2, were frequently mutated. Around 30,000 to 41,599 SVs were detected per sample. High-consequence tumour suppressor gene SVs were identified in EPHA3, CASP8, DMBT1, ZFHX3, and IRF5 gene. Common copy number tumour suppressor gene loss observed in RNH1, H19, CDKN1C, and others, suggesting their role in NPC carcinogenesis. Copy number gains were found in potential oncogenes such as Y RNA, LTO1, and FADD. Pathogenic short tandem repeats (STRs) in PABPN1 and RFC1 were identified in three samples, presenting a novel association with NPC. NPC sample which exhibited significant genomic instability had the shortest survival, potentially linked to multiple defective DNA repair genes. This study utilized long-read sequencing to identify a complex spectrum of genetic alterations, including numerous SVs and potentially pathogenic STRs, in Indonesian NPC. Extensive DNA repair gene defects, primarily complex SVs detectable by long reads, were observed and highly possibly associated with poor survival. These findings underscore the potential of long-read sequencing for uncovering clinically relevant mutations in NPC. © The Author(s) 2025.