Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of adult non-Hodgkin lymphoma, and high-risk patients are associated with poor outcomes and they may benefit from early identification, intensive treatment, and advanced therapeutic modalities. 18F-FDG PET/CT is recommended by international guidelines for staging of all 18F-FDG-avid lymphomas, leading to better informed treatment choices and altered management because of its capability to provide a comprehensive map of disease distribution and response assessment, particularly in extranodal disease. Moreover, PET/CT imaging impacts prognostication in DLBCL through its integration with clinical risk indices and also provides important information about tumor burden. This work reviews the most recent literature, examining the main prognostic indices currently used in clinical practice, those under evaluation in case studies, and the contribution of novel technological advances, with particular attention to semi-quantitative PET-based parameters such as TMTV and Dmax. PET/CT can also provide an accurate response assessment through visual and quantitative evaluation. Starting with the International Harmonization Project and the Deauville criteria, and considering the technological advances that have progressively improved image quality, this work explores the crucial role of PET/CT in assessing treatment response and its still-debated role in the initial evaluation of therapy in patients with DLBCL. Future PET-adapted strategies, including the use of alternative radiopharmaceuticals and hybrid imaging modalities, should aim to integrate early metabolic response with molecular profiling and tumor burden assessment. Efforts toward improved standardization and optimization of quantitative parameters are needed to enable robust validation across patient cohorts.