Cisplatin‐based chemotherapy is frequently employed as the primary therapeutic approach for advanced lung cancer. Nevertheless, a significant proportion of patients may develop resistance to cisplatin, leading to diminished efficacy of chemotherapy. Through analysis of Gene Expression Omnibus databases, TSPAN6 has been identified as a key factor in conferring resistance to cisplatin, attributed to its activation of the NF‐κB signaling pathway. Knockdown of TSPAN6 using siRNA resulted in decreased expression levels of NF‐κB in A549 cells. This indicates that TSPAN6 may have dual effects on lung cancer cisplatin resistance and could serve as a promising therapeutic target for individuals with cisplatin resistance.