As the pollution by heavy metal lead ion (Pb2+) and nitrite (NO2–) is becoming increasingly severe, the development of probes for hazardous Pb2+/NO2– is of great practical significance. Most of the reports regarding Pb2+/NO2– electrochemical probes are based on the involvement of active modifiers that can facilitate the detection of these two pollutants separately, and the active modifier for promoting both Pb2+/NO2– electrochemical probing has not been reported yet. Herein, by selecting cross-linked polyfluoreneisocyanide (PBIF) and vanillin/furfurylamine-based biomass benzoxazine (Va-Bz) as the starting substrates, a polyisocyanide derivative (PBIF-Va) with various N/O-containing motifs (amide, imine, tertiary amine, and phenolic −OH) was prepared by solid-state benzoxazine-isocyanide chemistry (ssBIC) postmodification. The elementary properties of PBIF-Va, such as the chemical structure and microscopic morphology, were characterized. The modified glassy carbon electrodes (GCEs) with PBIF-Va as the key modifier, PBIF-Va/Nafion/GCE and PBIF-Va/chitosan (CS)/GCE, were prepared, and their electrochemical response toward Pb2+ and NO2– was investigated here. Experimental results showed that compared with the precursor (PBIF)-containing electrodes (PBIF/Nafion/GCE and PBIF/CS/GCE), the modified electrodes with PBIF-Va as the modifier (PBIF-Va/Nafion/GCE and PBIF-Va/CS/GCE) exhibited stronger electrochemical responses toward both Pb2+ and NO2–, and the corresponding detection limits reached 0.054 μM (for Pb2+) and 0.38 μM (for NO2–), respectively.