A common feature of the outer layer of protective biological exoskeletons is structural anisotropy. Here, we directly quantify the mechanical anisotropy and fracture of an individual material layer of a hydroxyapatite-based nanocomposite exoskeleton, the outmost ganoine of Polypterus senegalus scale. Uniaxial compression was conducted on cylindrical micropillars of ganoine fabricated via focused ion beam at different orientations relative to the hydroxyapatite rod long axis (θ = 0°, 45°, 90°). Engineering stress versus strain curves revealed significant elastic and plastic anisotropy, off-axial strain hardening, and noncatastrophic crack propagation within ganoine. Off-axial compression (θ = 45°) showed the lowest elastic modulus, E (36.2 ± 1.6 GPa, n ≥ 10, mean ± SEM), and yield stress, σ(Y) (0.81 ± 0.02 GPa), while compression at θ = 0° showed the highest E (51.8 ± 1.7 GPa) and σ(Y) (1.08 ± 0.05 GPa). A 3D elastic-plastic composite nanostructural finite element model revealed this anisotropy was correlated to the alignment of the HAP rods and could facilitate energy dissipation and damage localization, thus preventing catastrophic failure upon penetration attacks.