Tensile deformation response of Fe40Mn40Co10Cr10 high entropy alloy (HEA) and equiatomic NiCoCr medium entropy alloy (MEA) single crystals were investigated at room temperature. TEM observations revealed that up to four deformation mechanisms govern the strain hardening in these alloys, depending on the crystallographic orientation of tensile loading: planar slip, dislocation substructure controlling the nucleation of twin/hcp lamellas, twinning, and hcp phase transformation. Consequently, the interaction of these mechanisms during deformation leads to a higher work hardening rate as compared to the orientations without twinning and phase transformation. Moreover, NiCoCr single crystals attain higher fracture strains and exhibit higher ultimate tensile strengths as compared to Fe40Mn40Co10Cr10. The TEM analysis showed that nanotwins and hcp lamellas are more prevalent at the early stages of deformation in the MEA, significantly enhancing the ductility, while the higher strength levels are associated with the high volume fraction of twins/hcp lamellas with relatively small thickness.