Introducing heavy halogen atoms into organic small molecules is a practical strategy for efficient singlet oxygen (1O2) generation. Generally, bromine or iodine atoms are introduced on the aza-boron-dipyrromethene (aza-BODIPY) core, rather than on the periphery aryl rings for efficient 1O2 generation. Herein, an aza-BODIPY dye NBDPBr with unexpected bromination on the periphery aryl rings was synthesized for photoacoustic (PA) imaging-guided synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) in tumor cells. Owing to unexcepted bromination at the periphery aryl rings, NBDPBr demonstrated an outstanding singlet oxygen quantum yield (ΦΔ) of 66% which was superior to similar brominated photosensitizers previously reported. After encapsulation with amphiphilic polymer F-127, hydrophilic NBDPBr nanoparticles (NPs) were fabricated and exhibited an excellent photothermal conversion efficiency (η) of 43.0% under 660 nm photoirradiation. In vivo PA imaging results demonstrated that NBDPBr NPs could specifically accumulate at tumor sites and realized the maximum tumor retention at 7 h post-injection. All the in vitro and in vivo results indicated the significant potence of NBDPBr with unexpected bis-bromination for PA imaging-guided synergetic PDT/PTT.