The arms race between bacteria and phages has driven the evolution of diverse antiphage defense systems. In recent years, a series of defense mechanisms targeting the nucleotide pool have been discovered, revealing that nucleotides are not only fundamental molecules for metabolism but also serve as key signaling carriers, effector substrates, and toxic weapons in bacterial immunity. According to the interaction modes between defense mechanisms and the nucleotide pool, this review systematically summarizes seven representative antiphage systems and categorizes them into three major classes: (1) Systems mediated by nucleotide cyclization into signaling molecules [e.g., cyclic oligonucleotide-based antiphage signaling system (CBASS), pyrimidine cyclase system for antiphage resistance (Pycsar), and Panoptes], which utilize nucleotidyltransferases to synthesize cyclic oligonucleotide second messengers that activate downstream effector proteins, leading to abortive infection; (2) Systems mediated by nucleotide depletion [e.g., deoxycytidine triphosphate (dCTP) deaminase, deoxyguanosine triphosphatase (dGTPase), and Nezha], which specifically hydrolyze or modify dNTPs or NAD⁺, resulting in a nucleotide pool imbalance and an energy crisis that block phage replication; (3) Systems mediated by aberrant nucleotide conversion [e.g., restriction by an adenosine deaminase acting on RNA (RADAR) and type III CRISPR-Cas-associated deaminase (CAAD)], which convert canonical nucleotides into toxic analogs [e.g., inosine triphosphate (ITP) and deoxyinosine triphosphate (dITP)], poisoning the nucleotide pool and inducing abortive infection. This review focuses on the core components, protein structural features, assembly mechanisms, and antiphage regulatory strategies of each category of system and discusses the escape mechanisms evolved by phages against these systems. In summary, the regulation of nucleotide pool homeostasis has emerged as a core strategy in bacterial immunity. In-depth investigation of these systems not only helps elucidate the molecular basis of prokaryote-phage co-evolution but also provides important insights for developing novel antimicrobial strategies and tools in synthetic biology.