The origin of odontogenic oro-facial infections is either periodontal infections or dental caries, which have expanded beyond the alveolar bone for the involvement of the facial spaces and face. An increasingly growing problem in treating infectious diseases is Multi-drug resistance (MDR). After the introduction of nanotechnology, silver nanpoarticles (AgNPs) have become immense antimicrobial agents. This investigation aimed to study the effect of AgNPs in treatment of Porphyromonas gingivalis- induced oro-facial infection in rats using routine histopathological evaluation and immuno-histochemical investigation of TNF-α. Thirty adult male albino rats were used and divided into three equal groups. Group I: served as control. Group II: were infected once by intramuscular injection the cheek mucosa opposite to upper right first molar with 1 × 109 CFU/mL of Porphyromonas gingivalis, and left for fourteen days. Group III: were subjected to the same procedure as group II then to daily injection at the site of infection with AgNPs (10 nm) with a concentration of 15μg/ml of distilled water for fourteen days. At the end of the experiment, the animals were euthanized, samples were taken from the cheeks at the site of infection, processed and stained. The results revealed P. gingivalis- induced orofacial infection resulted in extensive tissues destruction as well as massive expression of TNF-α. The treatment with AgNPs resulted in marked improvement of the suppuration and regression in the inflammation as well as withdrawal of TNF-α expression. The author concluded that it is possible to employ AgNPs as wide spectrum antimicrobials against Multi- drug resistance.