Depolymerization of plastics is a leading strategy to combat the escalating global plastic waste crisis through chemical recycling, upcycling, and remediation of micro-/nanoplastics. However, critical processes necessary for polymer chain scission, occurring at the polymer-catalyst or polymer-fluid interfaces, remain largely overlooked. Herein, we spotlight the importance of understanding these interfacial chemical processes as a critical necessity for optimizing kinetics and reactivity in plastics recycling and upcycling, controlling reaction outcomes, product distributions, as well as improving the environmental sustainability of these processes. Several examples are highlighted in heterogeneous processes such as hydrogenation over solid catalysts, reaction of plastics in immiscible media, and biocatalysis. Ultimately, judicious exploitation of interfacial reactivity has practical implications in developing practical, robust, and cost-effective processes to reduce plastic waste and enable a viable post-use circular plastics economy.