Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post‐neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER‐resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild‐type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue‐specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator‐activated receptor coactivator (PGC)‐1β, and Syvn1 mutants showed upregulation of PGC‐1β target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS‐102 abolished the negative regulation of PGC‐1β by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post‐translational regulator of PGC‐1β and a potential therapeutic target in obesity treatment.