Mark Twain’s novel fragment “3, 000 Years Among the Microbes” (1905) tells the story of the formerly human, now microbial protagonist “Huck” Bkshp. Huck reports from the retrospective of three thousand years of microbial time on the challenges of existence as a microbe in the body of the Hungarian immigrant and “tramp” Blitzowski. Migration and epi- and pandemic events enter into an often-fatal relationship. For many migrants, the desolate health care systems of their home countries were often one of the reasons for leaving in the first place. However, both during transit and on arrival at their destinations, they are exposed to no less precarious situations. Moreover, they are often perceived as a threat themselves. Against the backdrop of the lived pandemic experience of nineteenth-century cholera, Twain’s text depicts the hardships of migration in a literary original way and thus can be read as a paradigmatic literary manifest for the meeting point of transnational American studies and the Medical Humanities. In Twain’s novel fragment, the human-microbial protagonist Huck carries cholera, one of the deadliest pandemic threats of the nineteenth century. When immigrating into his host’s immigrant body, Blitzowski, he also becomes a carrier of the disease. That migrants bring fatal diseases is a topos not only in the (hi-)story of American immigration. Border closures and entry bans are often the first measures during disease outbreaks. However, epi- and pandemics cannot be excluded. As the impossibility of containment is a central topic of Twain’s narrative, I argue, it also can be seen as an early imagination of the emerging concept of “Planetary Health,” which, especially by focusing on recent microbiome research, rethinks the entanglements of human and more-than-human migrations in the face of current and future states of crisis.