Lung cancer is the leading cause of cancer‑associated mortality worldwide. Cisplatin (DDP) is a first‑line chemotherapeutic drug for the treatment of lung cancer; however, the majority of patients develop resistance to DDP. P‑glycoprotein (P‑gp), also referred to as multidrug resistance (MDR) protein 1, is associated with an MDR phenotype, which results in failure of cancer chemotherapy; thus, identifying effective MDR pump inhibitors may improve the outcomes of patients who develop resistance to treatment. Hesperetin is a derivative of hesperidin, which is extracted from tangerine peel and exhibits multiple antitumor properties. In the present study, human lung adenocarcinoma A549 and A549/DDP cells were treated with different concentrations of hesperetin and DDP, respectively. Furthermore, rhodamine 123 efflux assays, Cell Counting Kit‑8 assays, immunofluorescence, reverse transcription‑quantitative PCR and western blot analysis were used to elucidate the mechanisms underlying the effects of hesperetin On A549/DDP cells. Additionally, a xenograft model of lung cancer in nude mice was established to explore the effects of hesperetin on A549/DDP cell growth in vivo. The results demonstrated that hesperetin sensitized A549/DDP cells to DDP. In vivo, hesperetin pretreatment significantly inhibited tumor growth. Mechanistically, hesperetin markedly decreased the expression of P‑gp and increased the intracellular accumulation of the P‑gp substrate, rhodamine 123, in A549/DDP cells. In addition, pretreatment of A549/DDP cells with hesperetin significantly inhibited nuclear factor (NF)‑κB (p65) activity and its nuclear translocation. Taken together, the results of the present study suggest that hesperetin reversed P‑gp‑mediated MDR by decreasing P‑gp expression in A549/DDP cells, which was associated with inhibition of the NF‑κB signaling pathway. These findings may provide the basis for the use of hesperetin clinically to reverse MDR.