BACKGROUND: Nanomedicine offers a number of innovative strategies to address major public health burdens, including complex respiratory illnesses. In this work, we introduce a multi-drug nanoparticle fabricated using femtosecond laser ablation for the treatment of influenza, SARS-CoV-2, and their co-infections. METHODS: The SARS-CoV-2 antiviral, remdesivir; the influenza antiviral, baloxavir marboxil; and the anti-inflammatory, dexamethasone, were co-crystalized and then ablated in aqueous media using a femtosecond pulsed laser and subsequently surface modified with the cationic polymer, chitosan, or poly-d-lysine. Physical and chemical properties were then characterized using multiple complimentary techniques. Finally, a clinically relevant in vitro primary mouse trachea epithelial cell-air-liquid interface culture model was used to analyze the antiviral effect of our nanoparticles against Influenza Virus A. RESULTS: Our final nanoparticle exhibited a positive zeta potential with a diameter of ~73 nm. Remdesivir, baloxavir marboxil, and dexamethasone were all present in the nanoparticle suspension at a 1:1:1 ratio. Notably, these particles exhibited a potent anti-influenza effect, decreasing the viral titer by ≈ 4 logs in comparison to vehicle controls. CONCLUSION: Overall, these findings demonstrate great promise both for the use of laser ablation to generate multi-drug nanoparticles and for the anti-viral effects of our nanoformulation against respiratory illness.