Anticoagulant therapy is an important therapeutic tool for septic microcirculatory dysfunction. Low molecular weight heparin (LMWH) is a potent anticoagulant with antithrombotic properties, which is a crucial factor for sepsis treatment. However, it has a short plasma half-life and achieves low local concentrations; nanocomposite formulations may help overcome these limitations. Herein, it is aimed to determine if a functional layered double hydroxide (LDH)-LMWH nanocomposite improves microcirculation and organ function, while maximizing the antithrombotic effects and reducing bleeding risks in septic rats. This nanocomposite (fluorescein isothiocyanate (FITC)-fibrin antibody (Ab)-bovine serum albumin (BSA)-20LMWH-LDH) is constructed by intercalating LMWH and FITC into the LDH interlayer, and application of a BSA and an Ab coating onto the LDH nanoparticle surface. The nanocomposite released LMWH in a gradual and biphasic pattern, in an acidity-triggered manner. Capillary tubule studies and intestinal microcirculation investigations show that green fluorescent nanocomposites accumulated around microthrombi, validating their targeting ability. Animal experiments reveal that the nanocomposites significantly improve microcirculation in septic rats with minimal pathological damage to the heart, lung, liver, and kidney tissues. Thus, this study provides a novel strategy for the treatment of septic microcirculatory dysfunction in clinical situations.