Cancer phototheranostics involving optical imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) is a localized noninvasive approach in treating cancer. Mitochondria-targeted near-infrared (NIR) cyanines are excellent therapeutic photosensitizers of cancer. However, most mitochondria-targeted cyanines exist in the form of hydrophobic structures, which in vivo may cause cyanine aggregation during blood circulation, resulting in poor biocompatibility and limited therapeutic efficacy. Therefore, we developed a trade-off strategy by encapsulating mitochondria-targeted cyanines into liposomal bilayers (CyBI7-LPs), which balanced hydrophilicity that favored blood circulation and hydrophobicity that enhanced mitochondria tumor targeting. Moreover, CyBI7-LPs greatly minimized photobleaching of cyanine as self-generated reactive oxygen species (ROS) could rapidly escape from the liposomal bilayer, affording enhanced PTT/PDT efficacy. Bioorthogonal-mediated targeting strategy was further employed to improve uptake of tumor cells by modifying the liposomal surface to generate CyBI7-LPB. The CyBI7-LPB probe produced a tumor-to-background ratio (TBR) of approximately 6.4 at 24 HPI. Guiding by highly sensitive imaging resulted in excellent anti-tumor therapy outcomes using CyBI7-LPB due to the enhanced photothermal and photodynamic effects. This proposed liposomal nanoplatform exhibited a simple and robust approach as an imaging-guided synergistic anti-tumor therapeutic strategy.