Pseudomonas aeruginosa is one of the most worrisome infectious bacteria due to its intrinsic and acquired resistance against several antibiotics and the recalcitrance of its infections; hence, the development of novel antimicrobials effective against multidrug‐resistant P. aeruginosa is mandatory. In this work, silver nanoparticles obtained by green synthesis using a leaf extract and fungi were tested against a battery of clinical strains from cystic fibrosis, pneumonia and burnt patients, some of them with multidrug resistance. Both nanoparticles showed a potent antibacterial effect, causing severe damage to the cell wall, membrane and DNA, and inducing the production of reactive oxygen species. Moreover, the nanoparticles derived from fungi showed synergistic antibacterial effects with the antibiotics meropenem and levofloxacin for some clinical strains and both kinds of nanoparticles were nontoxic for larvae of the moth Galleria mellonella, encouraging further research for their implementation in the treatment of P. aeruginosa infections. Significance and Impact of the Study: The continuous rise of antibiotic resistance in bacteria such as Pseudomonas aeruginosa is a serious threat to human health, hence it is mandatory to identify novel ways to combat its infections. In this work, silver nanoparticles were synthesized in a green way using leaves and fugal extracts and its antibacterial effects were tested against clinical strains. The nanoparticles killed the strains due severe cellular damage affecting the membranes, the DNA and generating reactive oxygen species, in addition they were nontoxic and displayed synergy with some antibiotics; therefore, being a promising alternative to treat MDR P. aeruginosa infections.