Mitochondria play a key role in a variety of physiological processes, and mitochondria-targeting drug delivery is helpful and effective in cancer therapy. Rhodamine123 (Rhod123) and Doxorubicin (Dox) are not new chemical molecules, and they both can inhibit the growth of cancerous cells. Here, we combine these two "old" chemicals with polydopamine nanoparticles (PDA NPs) to strengthen the antitumor effect with the aid of near-infrared irradiation. PDA NPs carry these two chemicals tightly by hydrogen bonds and π-π stacking besides chemical bonds. The better antitumor profile of PDA-Rhod-Dox comes from the mitochondria-targeting delivery, which decreases ATP in living cells, causing apoptosis of cancerous cells effectively and inhibiting the growth of tumors in mice. The synergistic effect of PDA, Rhod123, and Dox improves the treatment effect of conventional chemotherapy drugs.