Microneedles (MNs) prepared from polymeric materials are painless and minimally invasive, safe and efficient, but they hindered by low mechanical strength and single diverse drug release pattern. Due to the distinctive mechanical strength and dimensions of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), the integration of nano-technology with microneedles can effectively improve penetration and delivery efficiency through the stratum corneum. We herein designed a simple paroxetine (PAX)-loaded PLGA nanoparticles-integrated dissolving microneedles system (PAX-NPs-DMNs), aiming to improve the bioavailability of PAX through the synergistic permeation-enhancing effect of dissolving microneedles (DMNs) and NPs. PAX-NPs-DMNs had a complete tips molding rate (N) of (94.06 ± 2.16) %, a 15×15 quadrangular-conical microneedle array and an overall fracture force of 301.10 N, which were improved nearly 0.50 times compared with the blank microneedles (HA-DMNs) and PAX microneedles (PAX-DMNs). PAX-NPs-DMNs could extend the release duration of PAX from 1 h to 24 h and the cumulative permeability per unit area (Q) was 47.66 times and 7.37 times higher than the PAX and the PAX-DMNs groups. PAX-NPs-DMNs could be rapidly dissolved within 10 min without hindering skin healing or causing adverse reactions. This study confirmed that PAX-NPs-DMNs can effectively improve the bioavailability of PAX and the mechanical strength of DMNs, which can easily penetrate the skin to provide sustained and painless delivery without causing adverse effects, thus offering a more convenient and effective method for central nervous diseases.