Obesity is found to be a significant risk factor for type 2 diabetes mellitus (T2DM), attributed to lipotoxicity‐induced β‐cell dysfunction. However, the specific mechanism involved in the process remains incompletely unclarified. The current study demonstrated lipotoxicity resulted in the activation of ER stress, which increased the protein level of TXNIP, thereby inducing senescence‐assiciated dysfunction in MIN6 cells under high fat environment. And we also found sesamol, a natural functional component extracted from sesame, was able to alleviate senescence‐associated β‐cell dysfunction induced by lipotoxicity by inhibiting ER stress and TXNIP. Our findings provided novel insights into senescence‐related T2DM and propose innovative therapeutic approaches for utilizing sesamol in the treatment of T2DM in the obese elderly population.