The prestressed reactive powder concrete beam (PRPCB) is an advanced structural member that can take full advantage of the ultra-high compressive strength of reactive powder concrete (RPC) and the high tensile strength of tendons. The fire safety of PRPCBs has been mainly studied at the material level, with relatively few experimental studies being conducted on the structural member level with the principal reason of serious fire-induced spalling. This paper proposed an innovative curing method to prevent RPC spalling under high stress and extreme heating rates. A total of eight full-scale beams were tested in ISO 834 fire, considering the parameters of the cover thickness of tendon, load ratio, partial prepressing ratio (PPR), and bonded and unbonded prestress classifications. Cross-sectional temperatures, mid-span deflections, effective prestressing, crack patterns, failure modes, and fire resistances of the beams were obtained. Subsequently, fine thermal–mechanical coupling nonlinear finite element (FE) models were developed and verified, and an extensive parametric study was performed to simulate the fire responses of PRPCBs. The results indicated that the load ratio, cover thickness, and sectional dimensions notably affected the fire safety of PRPCBs, and PRPCBs fabricated as under-reinforced beams at ambient temperature may fail as lightly reinforced beams under fire exposure. According to these parametric studies, Eurocode 2: BSEN 1992-1-2 might overestimate the fire resistance of PRPCBs with small sectional dimensions by up to 3–15%. Therefore, fire resistance suggestions for PRPCBs are presented in this paper.