An innovative process based on the combination of a UASB reactor and an IFAS system is proposed in order to combine different redox conditions and biomass conformations to promote a high microbial diversity. The objective of this configuration is to enhance the biological removal of organic micropollutants (OMPs) as well as to achieve the abatement of nitrogen by using the dissolved methane as an inexpensive electron donor. Results showed high removals of COD (93%) and dissolved methane present in the UASB effluent (up to 85%) was biodegraded by a consortium of aerobic methanotrophs and heterotrophic denitrifiers. Total nitrogen removal decreased slightly along the operation (from 44 to 33%), depending on the availability of electron donor, biomass concentration, and configuration (floccules and biofilm). A high removal was achieved in the hybrid system (> 80%) for 6 of the studied OMPs. Sulfamethoxazole, trimethoprim, naproxen, and estradiol were readily biotransformed under anaerobic conditions, whereas ibuprofen or bisphenol A were removed in the anoxic aerobic compartment. Evidence of the cometabolic biotransformation of OMPs has been found, such as the influence of nitrification activity on the removal of bisphenol A, and of the denitrification activity on ethinylestradiol removal.