Nuclear factor-kappaB (NF-kappaB), a redox-sensitive transcription factor, plays an important role in the aging process. Thus, developing and identifying specific components that modulate NF-kappaB without adverse side-effects would be of major importance. Hesperetin, a flavanone abundant in citrus fruits, has a variety of pharmacological properties being antioxidant, cholesterol-lowering, and anti-inflammatory. In this study, we investigated how hesperetin fed to 6- and 24-month-old rats modulates NF-kappaB in their kidneys. Results showed that hesperetin suppressed NF-kappaB activation and related gene expressions. An even more interesting finding is that hesperetin suppressed NF-kappaB through four signal transduction pathways, NIK/IKK, ERK, p38, and JNK. Further evidence showed the remarkable efficacy of hesperetin to suppress the translocation of Trx/Ref-1, indicating its beneficial effect on the redox status. The most significant findings of the current study report new information on the use of hesperetin as a potential anti-aging agent.