Cubic transition-metal carbides are high-melting compounds with remarkable high-temperature mechanical properties but are generally considered to be brittle at low-temperatures. Here, we report on the activation of multiple slip systems and plasticity in 001, 110, and 111 oriented vanadium carbide (VC) single-crystals subjected to uniaxial compression at room-temperature. Using in situ scanning electron microscopy based mechanical testing, we observe plastic strains up to 21 %, size-dependent yielding, and work hardening in VC(001) and VC(111). In comparison, VC(110) crystals are relatively brittle with limited localized plasticity. VC(111) crystals exhibit the highest yield strengths of up to ∼ 23.0 GPa while VC(001) crystals are some of the softest with yield strengths as low as ∼ 13 GPa. For loading along [110], we find that only the primary slip system, {111}〈11¯0〉, is active. In VC(001) and VC(111), we find the operation of two sets of slip systems, [{110}〈11¯0〉 and {111}〈11¯0〉] and [{111}〈11¯0〉 and {100}〈11¯0〉], respectively. Intriguingly, the estimated critical resolved shear stresses for all the three slip systems are nearly the same. Our results, which reveal orientation-dependent differences in the activity of the same slip system, provide new insights into plastic deformation in refractory compounds.