The secondary near-infrared region (NIR-II) fluorescence imaging-guided photothermal therapy (PTT) offers a noninvasive and light-controllable treatment option for deep-seated cancers. However, the development of NIR-II photothermal agents (NIR-II PTAs) that possess the desired properties of high molar absorption coefficient (ε), fluorescence quantum yield (QY), and photothermal conversion efficiency (PCE) remain a challenge due to the contradiction between radiative and nonradiative processes. Herein, we propose a novel side-chain heteroatom substitution engineering strategy to simultaneously enhance ε, QY, and PCE by modifying the molecular planarity. Remarkably, by increasing the number of oxygen atoms in the alkyl chains from DTIC, DO1TIC, to DO2TIC, the D-A interaction was enhanced and the molecular planarity was optimized. Theoretical calculations indicated that DO2TIC has a smaller energy gap and closer packing, which may lead to effective regulation of radiative and nonradiative transition processes. Notably, we achieved the excellent ε value of 2.61 × 105 M-1 cm-1 for the NIR-II PTA from DO2TIC, which is attributed to the enhanced molecular planarity. This value surpasses that of most previously developed NIR-II PTAs, resulting in boosted QY and PCE in its nanoparticle state. With these advantages, DO2TIC NPs demonstrated high signal-to-background ratio (SBR = 13.50) imaging of the vascular system and NIR-II imaging-guided PTT for effective tumor elimination using a 1064 nm laser. This study provides a new perspective for developing versatile NIR-II excited phototheranostic systems, enabling potent bioimaging and cancer therapy.