Widespread skin infections caused primarily by bacteria and yeast, pose a growing threat to healthcare systems. Phyto-photodynamic antimicrobial therapy is a promising treatment strategy with a few mild side effects for both superficial and deeper skin infections. The combination of natural plant products (polyphenols) with conventional photosensitizers makes it possible to improve the outcome of skin infections. In the present study, nanoengineered self-assembling bilosomes were used as a nanoplatform to deliver two compounds with different solubility, i.e., curcumin applied as a hydrophobic phytochemical compound and Methylene Blue used as a hydrophilic photosensitizer. Compared with the encapsulation of Methylene Blue alone, the double-loaded bilosomes (curcumin-supported Methylene Blue) showed higher efficiency in generating reactive oxygen species. Importantly, in our study, we also confirmed that bioinspired bilosomes prevent the rapid photobleaching of Methylene Blue, thereby enhancing its photoactivity. The post-irradiation antimicrobial action was tested against two pathogens - the Gram-positive bacterium (Staphylococcus aureus) and yeast (Candida albicans). The irradiation was provided after 10, 20, and 30 min, at a specific wavelength (λ = 640 nm) corresponding to 63, 126, and 189 J cm energy fluences. The most effective reduction in the microbial cells number was found 30 min post-irradiation and was 99.994% for double-loaded bilosomes compared to 99.989% killing S. aureus for bilosomes with Methylene Blue alone. For C. albicans fungal cells, the mortality was 99.669% in the presence of a Methylene Blue and curcumin mixture compared to 98.229% of those killed without the addition of curcumin. The overall results of our contribution provide evidence that curcumin in combination with MB enhances the photo-eradication efficiency of S. aureus and C. albicans planktonic cultures. Thus, the mixture of the phytochemicals with photosensitizers and their encapsulation in multifunctional bilosomes may contribute to the development of innovative antimicrobial phyto-photodynamic therapy in the future.