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Pyoderma gangrenosum (PG) is a rare ulcerative inflammatory dermatosis easily confused with wound infection following surgery. There have been seven case reports of PG occurring after total knee arthroplasty (TKA), all of which used routine tissue culture for differential diagnosis. Notably, all previous cases involved delayed diagnosis. We report a case of PG after TKA where we used shotgun metagenomics for differential diagnosis. Metagenomic analysis is a new method that can be used for pathogen detection; it is fast and sensitive, compared with traditional culture. Early application of metagenomic analysis in cases of suspicious wound infection after surgery can detect the pathogen of the infection for target therapy; it can also exclude infection for differential diagnosis of non-infectious diseases, such as autoimmune disorders. This case is presented to support the use of metagenomic analysis by surgeons and physicians for early and rapid differential diagnosis in patients who exhibit postoperative wound infections.