The development of efficient trace sensing and green photodegradation synergetic system for antibiotics has become increasingly significant in ecological environmental risk prevention. Herein, a recyclable self-cleaning surface-enhanced Raman scattering (SERS) hybrid system was developed by in-situ deposition of gold nanoparticles (Au NPs) on hydrogen-bonded organic framework (HOF) nanorods. The hybrid system possessed excellent trace SERS detection performance (10−13 M for rhodamine 6G), attributed to the considerable molecular enrichment capacity of HOFs and the intense local surface plasmon resonance (LSPR) effect of Au NPs. The hot-electron transfer pathway activated by the deposition of Au NPs extremely inhibited the hot carrier recombination and therefore induced a self-cleaning capacity of the hybrid system. Notably, the Au NPs decorated HOFs accomplished trace SERS sensing (10−10 M) for ciprofloxacin with good self-cleaning and reusable capabilities. This work provides a new material construction strategy for the reusable trace monitoring and green removal of antibiotics, possessed with an enormous application potential in ecological environmental risk prevention.