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FAM163A, a newly identified protein, is suggested to be part of the mitochondrial proteome, though its functions remain largely unknown. This study aimed to investigate the effects of <jats:italic>Fam163a<\/jats:italic> knockdown and mitochondrial dysfunction on food intake, AgRP neuron activity, and mitochondrial function in the hypothalamus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male C57BL\/6 and AgRP\u2010Cre mice received intracranial injections of either <jats:italic>Fam163a<\/jats:italic> shRNA, rotenone, or appropriate controls. Behavioral assessments included food intake, locomotor activity, and anxiety\u2010like behaviors. qRT\u2010PCR was used to quantify the expression of the genes related to food intake, mitochondrial biogenesis, dynamics, and oxidative stress. Blood glucose, serum insulin, and leptin levels were measured. Electrophysiological patch\u2010clamp recordings were used to assess the AgRP neuronal activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Fam163a<\/jats:italic> knockdown in the ARC increased the cumulative food intake in short term (first 7\u2009days) without altering the 25\u2010day food intake and significantly increased the <jats:italic>Pomc<\/jats:italic> mRNA expression. <jats:italic>Fam163a<\/jats:italic> silencing significantly reduced leptin levels. Both <jats:italic>Fam163a<\/jats:italic> knockdown and rotenone significantly reduced the firing frequency of AgRP neurons. Neither <jats:italic>Fam163a<\/jats:italic> silencing nor rotenone altered locomotor or anxiety\u2010like behaviors. <jats:italic>Fam163a<\/jats:italic> knockdown and rotenone differentially altered the expression of mitochondrial biogenesis\u2010, mitophagy\u2010, fusion\u2010, and oxidative stress\u2010related genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Hypothalamic FAM163A may play a role in modulating AgRP neuronal activity through regulating mitochondrial biogenesis, dynamics, and redox state. 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