Abstract | Yazeed A. Al‐Sheikh2 Unpredictable chronic mild stress (UCMS) leads to variable metabolic effects. Oxidative stress (OS) of adipose tissue (AT) and mitochondrial energy homeostasis is little investigated. This work studied the effects of UCMS on OS and the antioxidant/redox status in AT and mitochondrial energy homeostasis in rats. Twenty‐four male Wistar rats (180–220g) were divided into two equal groups; the normal control (NC) group and the UCMS group which were exposed to various stresses for 28 days. An indirect calorimetry machine was used to measure volumes Correspondence Mahmoud M. A. Abulmeaty, Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11362, KSA. Email: mabulmeaty@ksu.edu.sa Hazem K. Ghneim, Chair of Medical and Molecular Genetics, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11362, KSA. Email: hghneim@ksu.edu.sa Funding information Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, Grant/Award Number: IFKSURC‐1‐4409 of respiratory gases (VO2& VCO2), total energy expenditure (TEE), and food intake (FI). The AT depots were collected, weighed, and used for measuring activities and gene expression of key antioxidant enzymes (GPx1, SOD, CAT, GR, GCL, and GS), OS marker levels including superoxide anion (SA), peroxynitrite radical (PON), nitric oxide (NO), hydrogen peroxide (H2O2), lipid peroxides (LPO), t‐protein carbonyl content (PCC), and reduced/oxidized glutathione levels (GSH, GSSG). Additionally, AT mitochondrial fractions were used to determine the activities of the tricarboxylic acid cycle (TCA) cycle enzymes (CS, α‐KGDH, ICDH, SDH, MDH), respiratory chain complexes I–III, II–III, IV, the nicotinamide coenzymes NAD+, NADH, and ATP/ADP levels. Compared with the NC group, the UCMS group showed very significantly increased OS marker levels, lowered antioxidant enzyme activities and gene expression, as well as lowered TCA cycle and respiratory chain activity and NAD+, NADH, and ATP levels (p<.001 for all comparisons). Besides, the UCMS group had lowered TEE and insignificant FI and weight gain. In conclusion, AT of the UCMSsubjected rats showed a state of disturbed redox balance linked to disrupted energy homeostasis producing augmentation of AT. KEYWORDS adipose tissue, energy homeostasis, oxidative stress, unpredictable chronic mild stress (UCMS)