The rapid spread and mutation of SARS-CoV-2, the virus responsible for COVID-19, has set the foundation for extensive research into next-generation therapeutic strategies. A critical component of SARS-CoV-2 is the trimeric Spike (S) glycoprotein, which facilitates viral entry into host cells by interacting with the receptor-binding domain (RBD). To inhibit and block viral entry, we designed and developed molecularly imprinted synthetic nanogel antibodies (MIP-SNAs) that cap the Spike S1 RBD. This aims to provide a versatile, biosecure, and effective therapeutic tool for the prevention and treatment of SARS-CoV-2 infection. Herein, we employed reverse miniemulsion polymerization to synthesize MIP-SNAs using poly(ethylene glycol) diacrylate (PEGDA), a nontoxic, nonimmunogenic and FDA-approved polymer, able to interact noncovalently with the functional groups of template Spike S1 RBD. In addition, the formulation of MIP-SNAs was based on a preliminary investigation of protein conformation by circular dichroism. Characterization of the SNAs was conducted using several techniques to investigate the chemical structure, thermal stability, size, and morphology. Under optimal conditions, the MIP-SNAs exhibited high specificity, with rebinding capacities up to 6-fold higher compared to the control nonimprinted synthetic nanogel antibodies. MIP-SNAs also demonstrated notable selectivity toward the SARS-CoV-2 Spike S1 RBD protein compared to the structural resembling Spike proteins of Bat-CoV, while cytocompatibility assays confirmed the biocompatible character of the SNAs. Given the excellent features of the recently developed MIP-SNAs, we are one step closer to finding efficient but also patient-friendly prevention and treatment solutions for SARS-CoV-2 infection. Beyond immediate applications, this technology offers the potential for broader diagnostic and therapeutic uses against related viral pathogens.