Plastic pollution is a global concern due to the long half-life and high resistance of many synthetic plastics to natural biodegradation. Therefore, great effort is required to avoid littering. However, the challenge of managing the ever-increasing quantities of plastic waste is daunting. The biodegradation of synthetic plastics, such as polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), polyvinyl chloride (PVC), polystyrene (PS), and polyurethane (PUR) by microorganisms is either slow or under investigation as to whether it occurs at all in different environmental niches (e.g., soil, aquatic systems). There is an urgent need to complement the existing knowledge on the biodegradation and biotransformation of synthetic plastics to enable effective bioremediation strategies to mitigate the effects of environmental plastic contamination. Therefore, the aim of this review is to highlight current fundamental and applied research regarding the most promising biodegradation processes for synthetic plastics, the synthesis and applications of the most effective plastic-degrading enzymes, successful biotechnological strategies to improve degradation, such as enzyme engineering and novel reactor designs, and plastic waste bioconversion into value-added products. In addition, this review is intended to depict indications for techno-economic analyses toward the valorization of plastic biodegradation processes and the environmental impacts of synthetic plastic biodegradation. Combining strategies, such as enzymatic plastic degradation followed by microbial biotransformation with the broad array of available pretreatment methods and abiotic factors, can contribute, under confined conditions, to the end-of-life utilization of plastics, consequently leading to more efficient biorecycling processes, and hence, to a circular plastic economy.