Biofouling of polyamide membranes is one of the main barriers faced by reverse osmosis (RO) technologies to supply fresh water. Currently, biofouling is addressed by feed water pretreatment using chlorine, followed by membrane cleaning. Chlorine damages polyamide membranes and also generates harmful disinfection byproducts. Thus, safer strategies are needed to prevent biofouling in polyamide membrane systems. This review investigates the applicability of the following non-oxidizing biocides in preventing and controlling biofouling in RO systems, including their antimicrobial efficiency, hazard levels, membrane compatibility, and applicability to drinking water treatment: (1) 2,2-dibromo-3-nitropropionamide (DBNPA); (2) 2-methyl-4-isothiazolin-3-one (MIT); (3) sodium bisulfite (SBS), (4) phenoxyethanol (PE), (5) sodium benzoate (SB). According to this review, MIT and DBNPA present most of the features attributed to an ideal anti-biofouling chemical but also are the most hazardous biocides. Due to safety and efficacy, none of the five chemicals were determined to be the final solution to address membrane biofouling. However, alternative RO biocide research is in early development and requires further investigation via biofouling prevention studies. Therefore, future research efforts on the investigation of economic, eco-friendly, and safe antifouling agents to prevent and treat biofouling in RO systems are paramount to promote sustainable water supply in water-stressed countries.