Microneedle (MN), a smart transdermal drug delivery system (TDDS), is a promising novel technology to deliver various drugs having different physicochemical properties. Such an approach and innovative technology attracted the attention of researchers worldwide to further study and discover the new technology due to the multiple advantages MN offers as it is a non-invasive TDDS with a fast onset of action besides sustained release properties. The combination of nanotechnology with microneedles’ technology presents an innovative and novel promising strategy aiming to merge the advantages of both technologies to allow safe and effective delivery with improved skin permeability of various drugs for the treatment, prevention, and diagnosis of various diseases. Several types of microneedles have been designed to improve patient compliance and reduce the dose frequency using the sustained release property, such as solid MNs, coated MNs, dissolving MNs, and hydrogel-forming MNs. In this review, we will discuss some examples from the previous research conducted on polymeric nanoparticles loaded microneedles, Lipidic nanoparticles loaded microneedles, metallic nanoparticles loaded microneedles, and nanocrystals loaded microneedles. In addition, we will discuss the applications of nanoparticles loaded microneedles in Vaccines, cancer, and diabetes. Lastly, we will present the main limitations to transfer the Nanoparticles loaded microneedles from bench to market