Mastoiditis, a serious complication of acute otitis media, primarily affects the pediatric population and requires prompt diagnosis and treatment to prevent severe complications. This review explores the pathophysiology, clinical presentation, diagnostic techniques, and therapeutic approaches for mastoiditis, focusing on the role of amoxicillin in its management. The anatomical connection between the middle ear and mastoid air cells facilitates the spread of infection, which is further influenced by inflammatory processes, bacterial biofilms, and host immune responses. Diagnosis involves a combination of clinical findings, imaging studies such as computed tomography and magnetic resonance imaging, and microbiological cultures to guide targeted antibiotic therapy. Amoxicillin remains the first-line treatment for non-resistant cases owing to its effectiveness against common pathogens, safety profile, and cost efficiency. However, the increasing prevalence of β-lactamase-producing bacteria necessitates the use of amoxicillin-clavulanate in resistant cases. Antibiotic selection should be based on local resistance patterns and patient-specific factors, such as allergies and comorbidities. Surgical interventions, including mastoidectomy, are required in advanced or refractory cases. Future research should focus on developing novel diagnostic tools, optimizing antibiotic regimens, and implementing antimicrobial stewardship programs to combat drug resistance. Global collaboration is essential for establishing standardized guidelines and improving access to high-quality care in resource-limited settings.