Purpose: Thalassemia is a major public health concern in Southeast Asia, particularly in Malaysia, where a high carrier rate places significant pressure on healthcare systems. Hereditary Persistence of Fetal Hemoglobin (HPFH) and deltabeta (δβ) thalassemia are genetic conditions associated with elevated levels of fetal hemoglobin (Hb F). This study aimed to determine the frequency of common beta (β)-globin gene cluster deletions among Malaysian carriers of HPFH or δβ thalassemia, while also providing an overview of the thalassemia burden in the region. Methods: A retrospective study was conducted on 534 blood samples submitted to the Institute for Medical Research (IMR), Malaysia, for β-thalassemia genotyping between January 2017 and December 2019. Demographic data, including full blood count parameters and hemoglobin (Hb) analysis, were retrieved. Deoxyribonucleic acid (DNA) was extracted and analyzed using Multiplex Gap-Polymerase Chain Reaction (PCR) to detect large deletions in the β-globin gene cluster. Results: Seven distinct deletions were identified among the 534 heterozygous carriers. The two most common deletions were Gγ(Aγδβ)°-thalassemia Siriraj I (~ 118 kilobase pairs [kb]) and δβ°-thalassemia Thai (~ 12.5 kb), accounting for 30.0% and 29.8% of cases, respectively. The HPFH-6 deletion was observed in 20.0% of cases, followed by  Gγ(Aγδβ)°-thalassemia Asian-Indian Inversion-Deletion (Inv/Del) (14.2%), Gγ(Aγδβ)°-thalassemia Chinese (~ 100 kb) (4.3%), HPFH-3 (0.9%), and  Gγ(Aγδβ)°-thalassemia Asian (~ 49.3 kb) (0.7%). The ethnic distribution showed a predominance among Malay patients (93.4%), with specific deletions suggesting ethnic clustering. Genotype–phenotype analysis revealed notable variations in hematological parameters: carriers of HPFH-3 had the highest Hb F levels (25.3 ± 3.1%) as measured by high-performance liquid chromatography (HPLC) and showed the least severe microcytosis, while carriers of δβ°-thalassemia Thai (~ 12.5 kb) demonstrated more pronounced hematological abnormalities.Findings were consistent with previous reports from Southeast Asia, underscoring the importance of incorporating molecular diagnostics into national screening programs. Although Multiplex Gap-PCR is robust, further studies using Next-Generation Sequencing (NGS) and Multiplex Ligation-dependent Probe Amplification (MLPA) are recommended to detect rare or undetected mutations. Conclusions This study provides crucial data on the molecular spectrum of HPFH and δβ thalassemia in Malaysia, contributing to improved diagnostic strategies and genetic counselling. Future research should explore additional genetic variants to enhance national thalassemia prevention programs.