Tenofovir disoproxil fumarate, a key nucleotide analog reverse transcriptase inhibitor in antiretroviral therapy (ART), is essential for HIV and chronic hepatitis B management. Although TDF effectively suppresses viral replication, prolonged use can lead to renal and bone complications, including acute kidney injury, chronic kidney disease, and osteomalacia. This report highlights two cases illustrating Tenofovir disoproxil fumarate’s impact on bone health and renal function. A 48-year-old female with a 20-year HIV history on TDF-based Anti-Retroviral Therapy developed osteomalacia, experiencing pain and pseudo-fractures. Switching to abacavir improved her symptoms and lab markers rapidly. In a 61-year-old male, long-term TDF use led to an intertrochanteric femur fracture, renal impairment, and metabolic bone disease, requiring ART modification and supportive care. These cases emphasize the need for routine renal and bone health monitoring in TDF-treated patients. Early detection and timely ART adjustments can mitigate complications, improving outcomes and quality of life.