Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of B-cell lymphoma, representing a clinical and therapeutic challenge due to its unique presentation, histopathological features, and treatment response. It primarily affects young adults, with a significant female preponderance, and is characterized by a large anterior mediastinal mass that causes compressive symptoms. Despite its aggressive nature, PMBCL patients have a favorable prognosis, with a 5-year survival rate exceeding 80% when early remission is achieved through first-line therapy. Drawing on the significant scientific therapeutic advances over recent years, this review focuses on the evolving treatment strategies for PMBCL patients. Anthracycline- and rituximab-containing regimens are the mainstays of first-line approaches, often followed by mediastinal radiation therapy. However, concerns regarding long-term toxicities have led to a reevaluation of treatment protocols, suggesting that radiotherapy can be safely omitted in patients who achieve a complete metabolic response after induction therapy, according to a PET-guided approach. Furthermore, new targeted therapies such as PD-1 inhibitors and CAR-T cell immunotherapy, have shown promising results in refractory or relapsed PMBCL.