Low-energy miniemulsions enable the production of uniform nanodroplets for a wide range of applications without the need for using specialized equipment. However, low-energy miniemulsions are typically formed in the presence of a surface-active agent with a specific structure and property. In this work, we elucidate the role of a surface-active statistical copolymer, poly(N-(2-hydroxypropyl) methacrylamide-co-di(ethylene glycol) ethyl ether methacrylate) P(HPMA-co-DEGMA), in the formation of low-energy miniemulsions and reversible addition-fragmentation chain-transfer (RAFT) polymerization, enabling the design of a new series of surface-active statistical copolymers. In particular, we found that the HPMA/DEGMA ratio and copolymer molecular weight significantly affect the interfacial tension between water and styrene and as a result, the size of nanodroplets and the RAFT miniemulsion polymerization. Importantly, these findings allowed for the design and synthesis of novel surface-active statistical copolymers composed of DEGMA and various hydrophilic moieties that can also substantially lower the interfacial tension to below 12 mN m−1. Furthermore, the new copolymer of DEGMA with methacrylamide (MAAm) resulted in the smallest nanodroplet size. This copolymer was subsequently selected to trigger the RAFT polymerization of styrene yielding nanoparticles of different morphologies including worm balls, worms, and vesicles. This work sheds light on the role of surface-active statistical copolymers and significantly expands the availability of surface-active agents for low-energy miniemulsion and RAFT polymerization. © 2022 The Royal Society of Chemistry.