Prefabricated buildings are green and environment-friendly, with high construction efficiency. Concrete-filled steel pipe structures have high bearing capacity and strong deformation ability. Special-shaped column frame structures of prefabricated concrete-filled circular steel pipe with built-in lattice can give full play to the advantages of prefabricated buildings and concrete-filled steel pipe structures, with the advantage of high space utilization rate of special-shaped column structures. In order to study Seismic performance of frame in special-shaped columns of prefabricated concrete-filled circular steel pipe with built-in lattice, a full-scale middle frame model specimen with two floors and two spans was designed, and the failure mechanism of the specimen was obtained by low-cycle loading test. The hysteretic performance, deformation capacity, energy dissipation capacity and stiffness degradation of the specimen were analyzed. The results showed that the failure mechanism of the prefabricated concrete-filled steel tubular special-shaped column is a typical beam hinge mechanism, which meets the design requirements of “strong column and weak beam”. The special-shaped columns frame of built-in concrete-filled circular steel pipe has full hysteretic curve, good ductility and energy dissipation capacity, and stable stiffness degradation. When the specimen is damaged, the inter-story drift angle reaches 1/23, which is much higher than the limit requirement of elastic–plastic inter-story drift angle of 1/50 under strong earthquake. The existence of built-in concrete-filled steel pipe changes the bearing mechanism of the structure. After the external concrete falls off, the internal force of the structure redistributes, forming a stress system of built-in concrete-filled steel pipe truss. The post-cast joint between overlapping precast column and superposed beam and grouting connection joint between precast column and column sleeve are not damaged, and the fabricated joints are safe and reliable.