Background/Objectives: This study evaluates the diagnostic accuracy of [18F]fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) using bone marrow biopsy (BMB) and clinical follow-up as reference standards. It further identifies predictive factors for bone marrow involvement (BMI) in non-Hodgkin lymphoma (NHL) patients. Methods: NHL patients who underwent [¹⁸F]FDG PET and BMB at diagnosis in a tertiary cancer center were included in this study. Diagnostic accuracy was analyzed, and logistic regression was performed to identify BMI predictors using Stata software version 17. A retrospective analysis of 262 NHL patients was conducted. Results: Concordance rates between [¹⁸F]FDG PET and BMB and between [¹⁸F]FDG PET and clinical follow-up were 75.6% and 88.1%, respectively. The primary cause of discordance between [¹⁸F]FDG PET and BMB was the detection of extra-iliac focal hypermetabolic bone marrow lesions by [¹⁸F]FDG PET, which were negative on BMB. The sensitivity, specificity, and accuracy of [¹⁸F]FDG PET were 62.9%, 80%, and 75.6%, respectively, with BMB as a reference, and 74.1%, 97.5%, and 88.2%, respectively, with clinical follow-up as a reference. The focal bone marrow [¹⁸F]FDG pattern was the most reliable indicator of BMI. Univariate logistic regression showed that advanced NHL stage, elevated alkaline phosphatase, thrombocytopenia, leukopenia, and elevated lactate dehydrogenase were significant predictors of BMI. Multivariate analysis revealed advanced NHL stage and thrombocytopenia as clinical predictors. Conclusions: [¹⁸F]FDG PET is a reliable tool for assessing BMI, providing comprehensive total-body evaluation and identifying extra-iliac involvement beyond the scope of BMB. The collective interpretation of molecular imaging, clinical, and biochemical factors is crucial for predicting BMI.