<p>β-thalassemia and iron refractory iron deficiency anemia (IRIDA) are distinct hereditary causes of microcytic anemia. Their co-occurrence in the same individual is extremely rare and complicates diagnosis and management. This case series emphasizes on the importance of performing molecular analysis to define personalized therapeutic strategies. We report an Omani family with high level of interfamily marriages presenting with persistent microcytic hypochromic anemia, low ferritin levels, and partial transient response to intravenous iron therapy. Initial investigations suggested non-transfusion-dependent β-thalassemia due to persistently elevated HbF and a homozygous HBB promoter variant (NM_000518.5 (HBB):c.-121 C &gt; T). Whole-exome sequencing subsequently identified a novel homozygous TMPRSS6 missense variant (NM_001374504.1(TMPRSS6):c.1070G &gt; C, p.Cys357Ser), classified as likely pathogenic for IRIDA. Extensive family history revealed multiple relatives with unexplained iron deficiency requiring intravenous iron therapy and two cousins unnecessarily treated as transfusion-dependent thalassemia. After molecular confirmation, transfusions were discontinued, and the affected siblings were successfully managed with periodic IV iron therapy. This case series highlights the importance of comprehensive genomic evaluation in complex anemia presentations, particularly in consanguineous populations. The coexistence of β-thalassemia and IRIDA can obscure the clinical picture, delay appropriate therapy, and result in suboptimal therapies. Early integration of genomics is crucial for accurate diagnosis and optimal patient management.</p>