The COVID-19 pandemic has led to an unprecedented increase in pharmaceutical drug consumption and plastic waste disposal from personal protective equipment. Most drugs consumed during the COVID-19 pandemic were used to treat other human and animal diseases. Hence, their nearly ubiquitous presence in the soil and the sharp increase in the last 3years led us to investigate their potential impact on the environment. Similarly, the compulsory use of face masks has led to an enormous amount of plastic waste. Our study aims to investigate the combined effects of COVID-19 drugs and microplastics from FFP2 face masks on important soil processes using soil microcosm experiments. We used three null models (additive, multiplicative, and dominative models) to indicate potential interactions among different pharmaceutical drugs and mask MP. We found that the multiple-factor treatments tend to affect soil respiration and FDA hydrolysis more strongly than the individual treatments. We also found that mask microplastics when combined with pharmaceuticals caused greater negative effects on soil. Additionally, null model predictions show that combinations of high concentrations of pharmaceuticals and mask MP have antagonistic interactions on soil enzyme activities, while the joint effects of low concentrations of pharmaceuticals (with or without MP) on soil enzyme activities are mostly explained by null model predictions. Our study underscores the need for more attention on the environmental side effects of pharmaceutical contamination and their potential interactions with other anthropogenic global change factors.