Although photothermal therapy (PT) and photothermal-chemotherapy (PT-CT) treatments have been used to achieve complete ablation of solid tumors, they are often implemented at more than 50 °C under high intensity and using a high dose of NIR irradiation, concomitantly inducing heavy skin burning, tissue damage, and ugly scarring. Moreover, the residual tumor cells at the treated site cannot be completely eradicated, resulting in tumor recurrence and metathesis. These key obstacles have prohibited PT and PT-CT treatments from transitioning to clinical use, therefore achieving traceless ablation of solid tumors without recurrence is still a challenge for real applications. To balance hyperthermia and a high drug-loading capacity in polyprodrugs to achieve mild PT-CT, we rationally designed a novel type of intracellular pH and reduction-cleavable chlorambucil prodrug and synthesized high drug-loading polydopamine-chlorambucil conjugate nanoparticles (PDCBs). The PDCBs show good photothermal properties and demonstrate intracellular pH-, reduction-cleavable, and external near infrared (NIR)-triggered drug release profiles. Polydopamine-chlorambucil conjugate nanoparticles with 40 wt% CB (PDCB) and mild NIR irradiation could facilitate cellular internalization and subcellular trafficking, generating an excellent and synergistic antitumor effect in vitro. Pharmacokinetics and small animal fluorescent and photoacoustic imaging demonstrate that PDCB has a 3.6-fold longer blood circulation time compared to free CB and attained selective tumor accumulation, simultaneously inducing a 4.1-fold stronger photoacoustic signal than the control. By using one intravenous injection of PDCB and a single dose of mild NIR irradiation, this simple and mild PT-CT treatment achieved a non-discerned tumor on the sixth day, and traceless and complete ablation of a solid MCF-7 tumor without recurrence within 50 days, opening up a new avenue for precise cancer therapy with the potential for real applications.