The aim of this systematic review is to provide a comprehensive overview of the existing literature, comparing18F-fluorodeoxyglucose (FDG) and11C-methionine (MET) for the imaging of multiple myeloma (MM) with positron emission computed tomography (PET/CT). Relevant studies published from 2013 up to March 2023 were selected by searching Scopus, PubMed, and Web of Science. Selected imaging studies were analyzed using a modified version of the critical Appraisal Skills Programme (CASP). Ten studies encompassing 335 patients were selected. On a patient-based analysis, MET sensitivity ranged between 75.6% and 100%, resulting higher than that measured for FDG (0–100%). MET outperformed FDG for the detection of focal lesions, diffuse bone marrow involvement and mixed patterns. PET-derived parameters resulted higher for MET than for FDG, with a strong correlation with clinical variables (e.g., monoclonal component and beta-2-microglobulin levels, bone marrow infiltration, etc.), although FDG maintained a prognostic impact on outcome prediction. When compared to other tracers or imaging modalities, MET showed stronger correlation and inter-observer agreement than FDG. Although biased by the small cohorts and requiring confirmation through multicenter studies, preliminary findings suggest that MET–PET should be preferred to FDG for PET imaging of MM, or alternatively used as a complementary imaging modality. Some issues, such as tracer availability and the role of MET with respect to other emerging tracers (i.e.,68Ga-pentixafor,18F-FACBC and18F-FET), should be the topic of further investigations.