A variety of hematological diseases manifest in the bone marrow (BM), broadly characterized as BM failure (BMF). BMF can be caused by acute lymphoblastic leukemia (ALL), which results in an expansion of hypoxic regions in the BM. Because of this hypoxic presentation, there is potential for improved characterization of BMF through in vivo assessment of oxygenation in the BM cavity. Photoacoustic (PA) imaging can provide local assessment of intravascular oxygen saturation (SO2), which has been shown to correlate with pimonidazole-assessed hypoxia. This study introduces an optimized PA imaging technique to assess SO2 within the femoral BM cavity through disease progression in a murine model of ALL. Results show a statistically significant difference with temporal changes in SO2 (from baseline) between control and diseased cohorts, demonstrating the potential of PA imaging for noninvasive, label-free monitoring of BMF diseases.