Lenalidomide (Revlimid), an analogue of thalidomide, possesses potent cytokine modulatory capacity through inhibition of cytokines such as TNF‐α, a cytokine pivotal for the onset and development of complications in obesity and diabetes mellitus. This study was designed to evaluate the effect of lenalidomide on oxidative stress, protein and DNA damage in multiple organs in an ob/ob murine model of obesity. C57BL/6 lean and ob/ob obese mice were given lenalidomide (50 mg/kg/d, p.o.) for 5 days. Oxidative stress, protein and DNA damage were assessed using glutathione (GSH) to oxidized glutathione (GSSG) conversion, carbonyl formation and Comet assay, respectively. Apoptosis was evaluated using caspase‐3 activity and levels of Bax, Bcl‐2, Bip, Caspase‐8, Caspase‐9 and TNF‐α were assessed using western blot analysis. Our data revealed that lenalidomide treatment did not affect glucose clearance in lean or ob/ob mice. Obese mice displayed reduced GSH/GSSG ratio in liver, gastrocnemius skeletal muscle and small intestinal tissues, enhanced protein carbonyl formation, DNA damage and caspase‐3 activity in liver, kidney, skeletal muscle and intestines tissues, the effects of which were alleviated by lenalidomide with the exception of obesity‐associated DNA damage in liver and kidney. Western blot analysis revealed elevated TNF‐α, Bax, Bcl‐2, Bip, Caspase‐8, and Caspase‐9 in ob/ob mice with various degrees of reversals by lenalidomide treatment. Taken together, these data indicated that lenalidomide protects against obesity‐induced tissue injury and protein damage possibly associated with antagonism of cytokine production and cytokine‐induced apoptosis and oxidative stress. This article is protected by copyright. All rights reserved.