Lightweight high/medium-entropy alloys (H/MEAs) possess attractive properties such as high strength-to-weight ratios, however, their limited room-temperature tensile ductility hinders their widespread engineering implementation, for instance in aerospace structural components. This work achieved a transformative improvement of room-temperature tensile ductility in Ti-V-Zr-Nb MEAs with densities of 5.4–6.5 g/cm3, via ingenious composition modulation. Through the systematic co-adjustment of Ti and V contents, an intrinsic ductility mechanism was unveiled, manifested by a transition from predominant intergranular brittle fracture to pervasive ductile dimpled rupture. Notably, the modulated deformation mechanisms evolved from solitary slip toward collaborative multiple slip modes, without significantly compromising strength. Compared to equimolar Ti-V-Zr-Nb, a (Ti1.5V)3ZrNb composition demonstrated an impressive 360% improvement in elongation while sustaining a high yield strength of around 800 MPa. Increasing Ti and V not only purified the grain boundaries by reducing detrimental phases, but also tailored the deformation dislocation configurations. These insights expanded the applicability of lightweight HEAs to areas demanding combined high strength and ductility.