With the rapid growth of economics and nano-technology, a significant portion of the anthropogenic emissions of heavy metals and nanoparticles (NPs) enters wastewater streams and discharges to wastewater treatment plants, thereby potentially posing a risk to the bacteria that facilitate the successful operation of the enhanced biological phosphorus (P) removal (EBPR) process. Although some efforts have been made to obtain detailed insights into the effects of heavy metals and metal (oxide) nanoparticles [Me(O)NPs], many unanswered questions remain. One question is whether the toxicity of Me(O)NPs originates from the released metal ions. This review aims to holistically evaluate the effects of heavy metals and Me(O)NPs. The interactions among extracellular polymeric substances, P, and heavy metals [Me(O)NPs] are presented and discussed for the first time. The potential mechanisms of the toxicity of heavy metals [Me(O)NPs] are summarized. Additionally, mathematical models of the toxicity and removal of P, heavy metals, and Me(O)NPs are overviewed. Finally, knowledge gaps and opportunities for further study are discussed to pave the way for fully understanding the inhibition of heavy metals [Me(O)NPs] and for reducing their inhibitory effect to maximize the reliability of the EBPR process.