We have developed laser-activated perfluorocarbon nanodroplets containing copper sulfide nanoparticles (CuS NPs) for contrast-enhanced ultrasound and photoacoustic imaging. As potential clinical contrast agents, CuS NPs have favorable properties including biocompatibility, biodegradability, and enhance contrast in photoacoustic images at clinically relevant depths. However, CuS NPs are not efficient optical absorbers when compared to plasmonic nanoparticles and therefore, contrast enhancement with CuS NPs is limited, requiring high concentrations to generate images with sufficient signal-to-noise ratio. We have combined CuS NPs with laser-activated perfluorocarbon nanodroplets (PFCnDs) to achieve enhanced photoacoustic contrast and, more importantly, ultrasound contrast while retaining the favorable clinical characteristics of CuS NPs. The imaging characteristics of synthesized CuS-PFCnD constructs were first tested in tissue-mimicking phantoms and then in in vivo murine models. The results demonstrate that CuS-PFCnDs enhance contrast in photoacoustic (PA) and ultrasound (US) imaging. Upon systemic administration in vivo, CuS-PFCnDs remain stable and their unique vaporization provides sufficient PA/US contrast that can be further exploited for contrast-enhanced background-free imaging. The conducted studies provide a solid foundation for further development of CuS-PFCnDs as PA/US diagnostic and eventually therapeutic agents for clinical applications.