(1) Background: Strain elastography (SE) is an ultrasound-based technique able to non-invasively assess tissue elasticity, with malignant tissues being stiffer than normal tissues. The purpose of the study was to evaluate the diagnostic performance of SE to differentiate feline mesen-teric benign and malignant lymph nodes (LNs) using a multivariate approach including both SE results and B-mode ultrasound and color Doppler findings. (2) Methods: Feline enlarged mesenteric LNs were evaluated using B-mode ultrasound, color Doppler ultrasonography, and SE. Short-to-long axis ratios, borders, echogenicity, hilum, vascular flow distribution, elastographic patterns, and strain ratios were recorded. Histological and/or cytological diagnosis was available for each LN. (3) Results: A total of 88 LNs were included, 46 (52.3%) benign and 42 (47.7%) malignant; in the benign group, 40 LNs had a diagnosis of reactive hyperplasia (group A) and 6 eosinophilic sclerosing lymphadenitis (group B), while in the malignant group 42 had a diagnosis of lymphoma (group C). The principal component analysis approach showed evidence that by combining B -mode-and color Doppler-based scores with SE scores, the three groups of LNs can be accurately distinguished. (4) Conclusions: Our results demonstrate that a multivariate sonographic approach combining B-mode ultrasound, color Doppler ultrasonography, and SE can accurately distinguish benign from malignant LNs, thus helping in the clinical advice of feline patients.