The removal of pharmaceutically active compounds (PhACs) by fouled nanofiltration (NF) and reverse osmosis (RO) membranes has been extensively studied. Investigations on the effects of PhACs on organic fouling or biofouling in the NF/RO membrane application are still lacking. In this study, NF/RO membranes were fed with both synthetic (SRNOM solution and synthetic wastewater containing pure culture inoculum) and real (secondary effluent) water matrices spiked with three PhACs to elucidate the impact of PhACs on membrane fouling in comparison with control experiments in the absence of PhACs. Results showed that the PhACs mitigated flux decline during NF/RO filtration of SRNOM solution. The total organic foulants on both membrane surfaces decreased in the presence of PhACs due to the increased negative charges of the membranes and the enhanced size and charge effects of PhAC-macromolecule complexes in SRNOM solution. PhACs appeared to inhibit cell growth in the early stages of biofouling, causing a decline in total biomass, and then induced cell lysis, releasing EPS to protect from chemical stress in the later stages of biofouling, especially protein-like materials, causing more severe biofouling. The alleviation of declines in flux and salt rejection during the filtration of secondary effluent were found in the presence of PhACs. Therefore, we hypothesized that organic fouling or early-stage biofouling occurred during 100 h of filtration of secondary effluent. The decrease in PhAC retention was more obvious due to the higher ionic strength in the secondary effluent. This study may aid understanding of PhAC removal from various matrices and the effects of PhAC mixtures on membrane fouling by in practical NF/RO membranes applications.