Objective. This study aimed to observe the effect of hesperidin on the apoptosis, proliferation, and invasion of non-small-cell lung cancer, as well as to explore the possible mechanism. The inhibitory effect of hesperidin combined with carboplatin on non-small-cell lung cancer was also investigated. Methods. A549 and NCI-H460 cells were treated with different concentrations of hesperidin (10, 50, and 100 μM). The effect of siRNA knockdown on MDMX on the antitumor effect of hesperidin was observed. CCK-8 was used to detect cell activity. The apoptosis rate was determined by TUNEL. The transwell assay detects the ability of cell migration and invasion. The expression levels of the apoptosis-related proteins p53, MDM2, MDMX, p21, PUMA, Bcl-2, and Bax were detected by qRT-PCR. Cell-proliferation and transwell assays were used to detect the effects of the combined use of hesperidin and carboplatin on lung cancer cells. Results. Hesperidin significantly inhibited the activity and invasion of A549 and NCI-H460 cells in a dose-dependent manner. Hesperidin also induced the apoptosis of A549 and NCI-H460 cells. Hesperidin further inhibited the interaction between p53 and MDMX, increased the expression of p53, and played an anticancer role. The combination of hesperidin and carboplatin showed the most obvious antitumor effect. Conclusion. Hesperidin can inhibit lung cancer by inhibiting the interaction between p53 and MDMX. Moreover, the combination of hesperidin and carboplatin can inhibit the migration and invasion of lung cancer cell lines through p53 upregulation, thereby increasing the antitumor effect of carboplatin.