A series of multinary Cu-In-Zn-Se-S nanocrystals (NCs) are synthesized via a phosphine-free and one-pot approach, in which the Se powder and 1-dodecanethiol (DDT) are used as chalcogenide sources, respectively. The X-ray photoelectron spectra are used to confirm the presence of lattice sulfur in the as-obtained products. The emission color and the relative photoluminescence quantum yields of the Cu-In-Zn-Se-S NCs can be tuned by varying the Cu contents, the amount of Se powder, as well as the DDT dosage. In addition, the formation process of the multinary Cu-In-Zn-Se-S NCs is different from that of quaternary Cu-In-Zn-S NCs, which is dominated by the doping of Cu ions into the In-deficient In-Zn-Se-S NCs but not the partial interdiffusion of Zn2+ into the Cu-based NCs. This plausible deduction is based on the comparison of optical properties of the products synthesized using the hot-injection and one-pot methods. Furthermore, the performance of the solution-processed quantum-dot light-emitting diodes (QLEDs) using the Cu-In-Zn-Se-S NCs as emission layers is examined, and the QLEDs exhibit a high luminance over 1500 cd m−2 and a high peak current efficiency of ≈0.4 cd A−1 at 1000 cd m−2.