This research investigates the seismic performance of precast frame with ultra-high performance concrete (UHPC) composite beams and high-strength concrete (HSC) columns. An experimental study was conducted on two frame specimens with 1/2-scale, three-story, and two-bay: a precast UHPC-HSC composite frame (UHPC-HSC frame) and a fully cast-in-place concrete frame (RC frame). The precast UHPC-HSC frame consists of composite beams with precast U-shaped UHPC permanent beam formworks and cast-in-place beam cores, precast HSC columns, and cast-in-place UHPC connections. The results indicate that both frames exhibit a mixed sidesway mechanism with beam hinges dominating. The UHPC-HSC frame demonstrates better structural integrity and experiences smaller structural damage, making it more suitable for rapid repair after earthquakes. The hysteresis curves of both frames are plump. The load-carrying capacity of the UHPC-HSC frame is 15.78% higher than that of the RC frame. The UHPC-HSC frame exhibits better ductility and deformation capacity compared to the RC frame. The whole and interstory ductility coefficients of both frames are greater than 3.49. The energy dissipation capacity of the UHPC-HSC frame is superior to that of the RC frame. At θ = 4.5%, the cumulative energy dissipation value of the UHPC-HSC frame is 18.66% higher than that of the RC frame. The research results can provide a reference for the engineering application of precast UHPC-HSC frame with UHPC composite beams and HSC columns.