Acute lymphoblastic leukaemia (ALL) can mimic diverse musculoskeletal conditions, often resulting in diagnostic delays. Genetic predisposition to various cancer syndromes further complicates the clinical picture, influencing disease presentation and treatment response. We report an adolescent boy who presented with a 2-month history of episodic fever, persistent low back pain and non-migratory joint pain, with a history of growth failure, developmental delay and seizures since childhood. There was a history of malignancy in multiple family members. The clinical examination revealed no features suggestive of systemic involvement. The joint examination revealed swelling around the knee joints. Initial work-up for chronic infections and autoimmune diseases was negative. Magnetic resonance imaging spine findings of multiple T2 hyperintense lesions warranted a bone marrow examination, which confirmed the diagnosis of Ph+ B− ALL. Molecular analysis revealed a pathogenic heterozygous missense variant in the TP53 gene, leading to the diagnosis of Li-Fraumeni syndrome. This case highlights the importance of recognizing musculoskeletal symptoms as a potential presentation of ALL. Early consideration of leukaemia in the differential diagnosis can prevent delays in treatment, ultimately improving outcomes.