Early detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near‐infrared window (NIR‐II) has been regarded as a promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR‐II organic renal‐clearable probes are hampered by their low brightness (ϵmaxΦf>1000 nm<10 M−1 cm−1) and limited blood circulation time (t1/2<2 h), which impede the targeted imaging performance. Herein, we develop the aza‐boron‐dipyrromethene (aza‐BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmaxΦf>1000 nm≈60 M−1 cm−1), which is about 10‐fold higher than that of previously reported NIR‐II renal‐clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non‐invasively diagnosis of renal ischemia‐reperfusion injury (RIR) earlier than clinical serum‐based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2≈6.1 h) and higher brightness than traditional PEGylated renal‐clearable control fluorophores (t1/2<2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time. A series of bright NIR‐II brush macromolecular fluorophores (FBP) with high renal‐clearance efficiency and long‐blood circulation time has been developed. These achieve real‐time in vivo NIR‐II imaging of renal ischemia‐reperfusion injury, tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time.