Objective The aim of this study was to evaluate the role of diffusion-weighted imaging (DWI) and chemical shift imaging (CSI) for the differentiation of benign and malignant vertebral lesions. Methods Patients with vertebral lesions underwent routine magnetic resonance imaging (MRI) along with DWI and CSI. Qualitative analysis of the morphological features was done by routine MRI. Quantitative analysis of apparent diffusion coefficient (ADC) from DWI and fat fraction (FF) from CSI was done and compared between benign and malignant vertebral lesions. Results Seventy-two patients were included. No significant difference was noted in signal intensities of benign and malignant lesions on conventional MRI sequences. Posterior element involvement, paravertebral soft-tissue lesion, and posterior vertebral bulge were common in malignant lesion, whereas epidural/paravertebral collection, absence of posterior vertebral bulge, and multiple compression fractures were common in benign vertebral lesion ( p < 0.001). The mean ADC value was 1.25 ± 0.27 mm 2 /s for benign lesions and 0.9 ± 0.19 mm 2 /s for malignant vertebral lesions ( p ≤ 0.001). The mean value of FF was 12.7 ± 7.49 for the benign group and 4.04 ± 2.6 for the malignant group ( p < 0.001). A receiver operating characteristic (ROC) curve analysis showed that an ADC cutoff of 1.05 × 10 -3 mm 2 /s and an FF cutoff of 6.9 can differentiate benign from malignant vertebral lesions, with the former having 86% sensitivity and 82.8% specificity and the latter having 93% sensitivity and 96.6% specificity. Conclusion The addition of DWI and CSI to routine MRI protocol in patients with vertebral lesions promises to be very helpful in differentiating benign from malignant vertebral lesions when difficulty in qualitative interpretation of conventional MR images arises.