The clinical applications of natural anticancer drugs are being restricted by poor water solubility, fast clearance in the circulation, lack of targeting to tumor cells, and poor tissue penetration. To address these problems, in this study, we developed a novel lignin-based targeted polymeric nanoparticles (NPs) platform, folic acid-polyethylene glycol-alkaline lignin conjugates (FA-PEG-AL), via self-assembly for delivery of anticancer drug (hydroxyl camptothecin, HCPT). These lignin-based nanoparticles had moderate particle size (∼150 nm) with a narrow size distribution (PDI < 0.1), exhibited excellent biocompatibility, high drug loading efficiency (∼24.2 wt % of HCPT), prolonged blood circulation time (∼7-fold of free HCPT), and enhanced cellular uptake (∼5-fold of free HCPT). Besides, the drug biodistribution study confirmed preferred accumulation of FA-PEG-AL/HCPT NPs in tumor tissue. Subsequent tumor xenograft test revealed superior tumor suppression efficacy and reduced side effects of FA-PEG-AL/HCPT NPs compared with free HCPT. Therefore, the prepared lignin-based FA-PEG-AL/HCPT NPs would be a promising candidate for anticancer drugs delivery.