More than 8 billion tons of plastic waste has been generated, posing severe environmental consequences and health risks. Due to prolonged exposure, microplastic particles are found in human blood and other bodily fluids. Despite a lack of toxicity studies regarding microplastics, harmful effects for humans seem plausible and cannot be excluded. As small plastic particles readily translocate from the gut to body fluids, enzyme-based treatment of serum could constitute a promising future avenue to clear synthetic polymers and their corresponding oligomers via their degradation into monomers of lower toxicity than the material they originate from. Still, whereas it is known that the enzymatic depolymerization rate of synthetic polymers varies by orders of magnitude depending on the buffer and media composition, the activity of plastic-degrading enzymes in serum was unknown. Here, we report how an engineered PETase, which we show to be generally trans-selective via induced fit docking, can depolymerize two different microplastic-like substrates of the commodity polymer polyethylene terephthalate (PET) into its non-toxic monomer terephthalic acid (TPA) alongside mono(2-hydroxyethyl)terephthalate (MHET) in human serum at 37 °C. We show that the application of PETase does not influence cell viability in vitro. Our work highlights the potential of applying biocatalysis in biomedicine and represents a first step towards finding a future solution to the problem that microplastics in the bloodstream may pose.