The integration of multiple therapeutic agents within a single nano-drug carrier holds promise for advancing anti-tumor therapies, despite challenges posed by their diverse physicochemical properties. This study introduces a novel multi-stage microfluidic co-encapsulation platform designed to address these challenges. By carefully orchestrating the nano-precipitation process sequence, this platform achieves sequential encapsulation of two drugs with markedly different physicochemical characteristics. Using the multi-stage microfluidic TrH chip, hybrid nanoparticles (HNPs) loaded with paclitaxel (PTX)-simvastatin (SV), PTX-lenvatinib (LV), and SV-LV were synthesized. Unlike conventional Bulk methods and existing commercial microfluidic Tesla and Baffle chips, the HNPs produced here exhibit a core-shell structure and uniform particle size distribution, crucial for enhancing drug delivery efficacy. Notably, this method achieves nearly 100 % encapsulation efficiency for both drugs across a dual-drug feed ratio range from 1:4 to 4:1. Drug loading efficiencies were quantified for PTX-SV/HNPs (14.97 ± 1.19 %), PTX-LV/HNPs (16.58 ± 0.69 %), and SV-LV/HNPs (19.21 ± 2.38 %). PTX-SV/HNPs demonstrated sequential release characteristics of SV and PTX, as confirmed by in vitro drug release experiments. Significantly, PTX-SV/HNPs exhibited superior cytotoxicity against HepG2 cells compared to individual PTX and SV treatments, underscoring their potential in cancer therapy. In conclusion, the developed multi-stage microfluidic platform represents a robust strategy for co-encapsulating drugs with substantial physicochemical disparities, thereby offering a promising avenue for advancing multi-drug delivery in nanomedicine applications.