The development of a multifunctional cancer diagnosis and treatment platform offers excellent prospects for the effective eradication of malignant solid tumors. Herein, a doxorubicin hydrochloride (DOX)-loaded tannic acid (TA)-coated liquid metal (LM) multifunctional nanoprobe was synthesized and applied as a highly efficient platform for the photoacoustic (PA) imaging-guided photothermal/chemotherapy of tumor. The multifunctional nanoprobes exhibited strong near-infrared absorption, a remarkable photothermal conversion efficiency (PCE) of 55%, and high DOX loading capacity. Combined with the large intrinsic thermal expansion coefficient of LM, highly efficient PA imaging and effective drug release were realized. The LM-based multifunctional nanoprobes were specifically adsorbed into the cancer cells and tumor tissues via glycoengineering biorthogonal chemistry. The in vitro and in vivo photothermal/chemo-anticancer activity confirmed their promising potential in cancer treatment. The subcutaneous breast tumor-bearing mice completely recovered in 5 days under light illumination with clear PA imaging presentation, which showed better antitumor outcomes than single-mode chemotherapy or photothermal therapy (PTT), while keeping side effects at a minimum. Such an LM-based PA imaging-guided photothermal/chemotherapy strategy provided a valuable platform for resistant cancer precise treatment and intelligent biomedicine.