<p>This study aimed to develop functionalized multi-walled carbon nanotubes (FMWCNTs) conjugated with chitosan (CHI) to enhance the drug-loading efficiency of methotrexate (MXT) and quercetin (QCT) separately. These formulations were designed into a capsule dosage form to achieve synergistic therapeutic effects for rheumatoid arthritis. The FMWCNTs-CHI composites loaded with MXT and QCT were optimized using a factorial design to achieve desired particle size, drug loading efficiency, and release profiles. Characterization confirmed strong drug–carrier interactions, thermal stability, nanoscale morphology, and elemental composition using FTIR, NMR, DSC, TGA, SEM, TEM, and XPS analyses. Optimized FMWCNTs-CHI-MXT and -QCT showed particle sizes of 124.5 and 143.1 nm, with high drug loading and &gt; 96% release. Moreover, in vivo studies in the RA model demonstrated that the FMWCNT–CHI formulations, particularly the combination of methotrexate and quercetin (MXT + QCT), led to a marked reduction in pro-inflammatory markers, TNF-α (351.33 ± 5.93 pg mL⁻¹) and CRP (0.19 ± 0.21 mg L⁻¹), compared to the disease control (1647.95 ± 0.00 pg mL⁻¹ and 2.27 ± 0.19 mg L⁻¹, respectively) and to the individual drug-loaded formulations, suggesting a potential synergistic anti-inflammatory effect resulting from the co-delivery strategy. A comparative analysis between the FMWCNT-CHI-MXT-QCT group and a dose-reduction group revealed a synergistic effect, with improved therapeutic outcomes at a lower dose of the drug. These findings suggest that FMWCNT-CHI composites offer potential for RA treatment. These findings underscore the system’s translational potential for RA therapy and warrant further investigation into long-term stability and targeted delivery strategies.</p> Graphical Abstract <p></p>