This study will determine if the drug, tecovirimat, helps treat people you are infected with monkeypox virus. You must be 18 years of age or older to participate. You must have a positive laboratory test for monkeypox virus within 14 days of enrolling in the study and at least one skin lesion. Participants with severe disease, significant skin conditions, participants with severe immune suppression will receive open-label tecovirimat. Participants who are pregnant or breastfeeding will receive open-label tecovirimat after discussion of the potential risks and benefits. Participants less than 18 years of age will receive open-label tecovirimat. Participants receiving a potent inducing concomitant medication will receive open-label tecovirimat. Once enrolled, study drug administration will be for 14 days. Participants will self-monitor skin and/or mucosal lesions daily through 29 days or resolution (whichever comes first), complete a daily diary of symptoms and complete a daily numerical rating scale for pain assessment. Participants will be seen weekly through day 29 for assessment of HMPXV disease, safety assessments, HMPXV sampling similar to that described for entry, and swabbing of new HMPXV lesions. Participants will be seen at day 57 to assess for possible recrudescence of infection (i.e., new lesions occurring after initial resolution of disease.