Wastewater treatment plants (WWTPs) provide a barrier against the discharge of contaminants of emerging concern (CECs) into the environment. The removal of CECs is highly WWTP-specific and the underlying mechanisms are still poorly understood, hampering the optimization of biological treatment steps for their removal. To fill this knowledge gap, we assessed the influence of four operational parameters of activated sludge biological treatment, namely total suspended solids, temperature, pH and redox conditions, on the sorption and biodegradation of four CECs under controlled laboratory conditions. Design of Experiments was used to better address the factors influencing CECs removal and interactions among operational parameters. The derived statistical models showed results in concordance with previous studies and indicated how sorption and biodegradation of the investigated CECs depend on most tested parameters and few of their interactions. The predictions of the developed models have been compared with literature values, indicating how the tested parameters are responsible for most of the variability of sorption, while they could not reliably generalize biodegradation rates. The developed models were also implemented as an extension of a mechanistic biological treatment model, successfully describing the dynamic behaviour of a large-scale WWTP, which was observed during a three-day continuous monitoring campaign. Compared to a traditional modelling approach, the one including the developed models showed on average almost a three-fold uncertainty reduction, favouring its use to aid WWTP managers and regulators for improved assessment of CEC fate and removal. Finally, the models highlighted that, while higher temperatures and solids concentrations generically favoured CECs removal, removal efficiency vary significantly due to operational parameters and no globally optimum conditions for CECs removal exist. The use of these models opens the door to the combined dynamic management of both traditional contaminants and CECs in WWTPs.