The current study investigated the effects of hydrothermal liquefaction (HTL) operated under a range of operating conditions on the fate of bioactive contaminants (BACs) often present in wastewater sources. HPLC analysis of BACs before and after HTL treatment showed essentially complete removal of BACs in presence of biomass feedstocks when HTL was operated at 300°C and ≥30 min. Tracking 14C for two BACs showed that 60–79% of the carbon was transferred to the HTL raw oil product, and most of the rest was found in the aqueous product. High-efficiency transformation experiments showed complete deactivation of antibiotic resistant materials for all tested HTL conditions. Due to the high temperature and pressure of HTL process, BACs are broken down into a variety of organic compounds that are present in the aqueous HTL product. Experiment data showed that 51% and 96% of these compounds can be removed by algal bioreactor and catalytic hydrothermal gasification treatments, respectively. Thus, HTL can effectively destruct a wide variety of BACs and help to reduce or eliminate any negative impacts of these compounds on human health and natural ecosystems.