Small-cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid proliferation, early metastasis, and frequent recurrence, which contribute to a poor prognosis. SCLC is defined by the near-universal inactivation of key tumor suppressor genes, notably TP53 and RB1, which play central roles in its pathogenesis and resistance to therapy. The p53 family of proteins, including p53, p63, and p73, is essential to maintaining cellular homeostasis and tumor suppression. TP53 mutations are almost ubiquitous in SCLC, leading to dysregulated apoptosis and cell cycle control. Moreover, p73 shows potential as a compensatory mechanism for p53 loss, while p63 has a minimal role in this cancer type. In this review, we explore the molecular and functional interplay of the p53 family in SCLC, emphasizing its members' distinct yet interconnected roles in tumor suppression, immune modulation, and therapy resistance. We highlight emerging therapeutic strategies targeting these pathways, including reactivating mutant p53, exploiting synthetic lethality, and addressing immune evasion mechanisms. Furthermore, this review underscores the urgent need for novel, isoform-specific interventions to enhance treatment efficacy and improve patient outcomes in this challenging disease.