Background: The purpose of this manuscript is to provide a comparative overview of the two global pandemics: the first on June 11th 2009 due to influenza A H1N1 (H1N1-09); the second and current pandemic caused by coronavirus 2019 (COVID-19) on March 11th 2020, focusing on how autopsy can contribute to the definition of cellular pathology, to clinical pathology and, more generally, to public health. Methods: A systematic literature search selection was conducted on PubMed database on June 5, 2021, with this search strategy: (COVID-19) AND (H1N1 influenza) showing 101 results. The following inclusion criteria were selected: English language; published in a scholarly peer-reviewed journal; full-length articles were further elected. To further refine the research was to focus on the type of manuscript: review, systematic review, and meta-analysis. A critical appraisal of the collected studies was conducted, analyzing titles and abstracts, excluding the following topics: treatment, public health measures and perception of the general population or healthcare personnel about their quality of life. According to these procedures, 54 eligible studies were included in the present review. Results: Histopathological findings play a key role in understanding the pathophysiological mechanisms of diseases and, thus possible therapeutic approaches. The evidence on the thrombo-inflammatory mechanism underlying COVID-19 is growing to a much greater magnitude than the diffuse alveolar damage in common with H1N1-09; our study appears to be in line with these results. The prevailing scientific thinking to explain the morbidity and mortality of COVID-19 patients is that it elicits an exuberant immune reaction characterized by dysregulated cytokine production, known as a “cytokine storm”. Conclusions: The histological and immunohistochemical pattern demonstrated similarities and differences between the infectious manifestations of the two pathogens, which justify empirical therapeutic approaches, in the first phase of the COVID-19 pandemic. Therefore, the previous pandemic should have taught us to promote a culture of clinical and forensic autopsies in order to provide timely evidence from integration among autopsy and clinical data for early adopting adequate therapies.