<p>The directional modulation of hydrogen-bonding networks serves as a pivotal strategy for optimizing the thermal stability of crystalline materials. In this study, four guanidinium-based hydrogen-bonded organic frameworks (HOFs)—guanidinium hydroquinone ([GUA][HYD]), guanidinium phloroglucinol ([GUA][PHL]), guanidinium terephthalic acid ([GUA][TER]), and guanidinium trimesic acid ([GUA][TRI])—were designed and synthesized by tailoring the acidic strength and substituent topology of anionic ligands, systematically investigating the hydrogen-bonding network’s impact on their crystal structures and properties. Single-crystal X-ray diffraction combined with Hirshfeld surface analysis revealed that N-H···O hydrogen bonds dominate the assembly of all HOFs, yielding two distinct topologies: a periodically layered framework ([GUA][HYD]) and a highly symmetric octameric cage-like architecture ([GUA][TRI]). In contrast, [GUA][PHL] and [GUA][TER] formed guest-incorporated configurations due to disordered hydrogen-bond directionality. Thermogravimetric analysis and density functional theory (DFT, B3LYP/6-311++G(d,p)) demonstrated that hydrogen-bond strength, density, and network symmetry critically govern thermal stability. Carboxylate-substituted systems ([GUA][TER]/[GUA][TRI]) exhibited better stability over phenolic hydroxyl analogs ([GUA][HYD]/[GUA][PHL]), attributed to enhanced hydrogen-bond interactions and three-dimensional ionic synergy. Furthermore, high-symmetry frameworks ([GUA][HYD] and [GUA][TRI]) outperformed their counterparts ([GUA][PHL] and [GUA][TER], respectively) in stability due to their highly ordered packing modes. This work reveals the inherent correlation between hydrogen-bond coordination, topological configuration, and thermodynamic behavior, probably providing theoretical support for the rational design of HOFs and advancing their applications in energy storage, catalysis, and controlled drug delivery.</p> Graphical Abstract <p></p>