It is a theoretical and technical challenge to construct well-defined nanostructures such as vesicles from fully hydrophilic homopolymers in pure water. In this paper, we incorporate one terminal alkynyl group into a fully hydrophilic linear or non-linear homopolymer to drive its unusual self-assembly in aqueous solution to form multicompartment vesicles, spherical compound micelles, flower-like complex particles, etc., which have been confirmed by transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic/static light scattering (DLS/SLS) and drug encapsulation experiments. The formation of poly(N-isopropyl acrylamide) (NIPAM) and poly[oligo(ethylene glycol) methacrylate] (POEGMA475) self-assemblies is mainly determined by the terminal alkynyl group itself (typically 1–3 wt%) while it is independent of other factors such as traditional hydrophobic–hydrophilic balance. Moreover, upon increasing the chain length of PNIPAM homopolymers, multicompartment vesicles, spherical micelles, and large flower-like complex particles can be obtained during the self-assembly process. In contrast, smaller micelles were formed when the kind of terminal alkynyl group attached to the PNIPAM chain was changed from a propargyl isobutyrate group to a (di)propargyl 2-methylpropionamide group. Particularly, a long chain hyperbranched structure with lots of terminal alkynyl groups induces the formation of vesicles. Also, the encapsulation experiment of doxorubicin hydrochloride was employed to further distinguish vesicular and micellar nanostructures. Additionally, the terminal alkynyl group-driven self-assembly has been applied to hydrophilic POEGMA475 homopolymers to afford similar nanostructures to PNIPAM homopolymers such as multicompartment vesicles and spherical compound micelles. Our study has opened up a new way to prepare hydrophilic homopolymer self-assemblies with tunable morphology.