Biofouling is a common challenge for underwater sensors, especially for long-term in situ monitoring in marine environments. In this study, we assessed the antifouling efficacy of a paint containing a natural product camptothecin (CPT) on six materials (316 L stainless steel, TC4 titanium alloy, 7075 aluminum alloy, polyoxymethylene, polyvinyl chloride, and Teflon), which are frequently used in the construction of underwater sensor housings. Additionally, a buoy-based sea-trial was performed to test the antifouling performance of the CPT-based paint on housings of three in situ sensors used for practical seawater monitoring applications, namely a spectrophotometer for chemical oxygen demand (COD) measurements and two fluorimeters for biochemical oxygen demand (BOD) and chlorophyll a (Chl a) concentration measurements. The results showed significantly lower macrofouling coverage on the areas painted with the CPT-based paint compared to the unpainted areas for each tested material over 9 months of seawater immersion. The CPT-based paint exhibited different antifouling performance for the different materials; in particular, it exhibited better antifouling performance on the plastic materials compared to the metal materials. Furthermore, when applied on submersible sensor housings in the sea-trial test, the CPT-based paint kept the housings of the COD sensor and the Chl a sensor clean for over 4 months. In addition, the paint prevented fouling of the BOD sensor housing even after 6 months of seawater immersion. Thus, our results suggest that the CPT-based paint could be used as a potential solution to control the biofouling of sensor housings for long-term in situ applications in marine environments.