Chemotherapy resistance remains a large obstacle to successful clinical cancer therapy, mainly due to little accumulation and low sensitivity of drugs and the effective clinical strategy still lacks. Herein, a novel yet simple strategy to combat cancer drug resistance using the plasmonic feature-based photothermal properties is reported. Rather than directly killing cancer cells using nanoparticle-mediated hyperthermia, for the first time, localized plasmonic heating of gold nanorod at a mild laser power density can modulate the drug-resistance related genes. This photothermal effect triggers higher expression of heat shock factor (HSF-1) trimers and depresses the expression of P-glycoprotein (Pgp) and mutant p53. In turn, both drug accumulation in the breast cancer resistant cells (MCF-7/ADR) and their sensitiveness to drugs can be greatly enhanced. Considering the universality and feasibility of this strategy, it points out a new unique way to challenge drug resistance.