Conventional phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is often limited by the risk of serious photodamage and shallow tissue caused by the excitation light. Lanthanide-doped upconversion nanoparticles (UCNPs) enable to convert long-wavelength light to short-wavelength emission, which, in principle, can address these issues in phototherapy. However, traditional UCNPs are mainly excitable in the near-infrared I region (700–900 nm), which still faces challenges such as strong light absorption/scattering and overheating side effects. Herein, we have developed an Er3+-sensitized upconversion nanoparticle (NaErF4@NaYbF4@NaYF4) in response to 1550 nm excitation light in the far NIR-II region. Through a core–shell–shell engineering strategy, the emissive signal of Er3+ ion can be finely tailored from red-dominant to green-dominant, offering great flexibility in optical tuning of Er3+ sensitized UCNPs under 1550 nm light excitation. Upon surface modification by a mesoporous silica shell and loading of dual photosensitive agents (MC540 (merocyanine 540) and FePc (iron phthalocyanine)), a synergistic PDT/PTT phototherapeutic nanoagent was constructed. Results showed that as-developed nanotherapeutic platform could solve the overheating problem and further enhance tissue penetration upon illumination by 1550 nm light, thus demonstrating great efficiency of combinational PDT/PTT for tumor treatment.