A prestressed concrete cast-in-situ continuous box girder bridge faces transverse cracking of the bottom plate of the second span and the overall stiffness decline. To address this issue, this paper analyzed the causes of the damage. A finite element damage model considering the reduction of section stiffness and prestress loss was established, and the new prestress reinforcement degree was reasonably determined according to the principle of envelope design. An internal and external prestress reinforcement scheme was proposed, which included adding a long internal bundle to the outer web and adding a partial short external bundle to the bottom plate of the second span. Through construction monitoring and comparison of load tests before and after reinforcement, the precompression stress reserve was restored; the overall stiffness was improved, and the reinforcement effect was good. The internal and external prestress reinforcement technology has the advantages of effectively improving the stress condition and increasing the overall stiffness of the structure. It has wide adaptability and can be used as a reference for reinforcement of other similar projects.