Primary central nervous system lymphoma (PCNSL) is an uncommon type of non-Hodgkin lymphoma confined to the central nervous system, presenting with diverse clinical manifestations, including neuropsychiatric symptoms. This case report describes the diagnostic process of PCNSL in a 76-year-old patient with bipolar disorder type II, who had been in long-term remission, presenting with a depressive episode accompanied by rapidly progressive cognitive impairment and psychotic symptoms following a sudden and traumatic personal loss. The case highlights the challenges in diagnosing PCNSL when psychiatric symptoms dominate the clinical presentation. Additionally, potential risk factors for PCNSL, the association between tumor characteristics and neuropsychiatric symptoms, as well as current insights into prognosis, have been reviewed to facilitate the planning of a multidisciplinary treatment approach.