Attention to cases of death in custody and their prevention is an issue of increasing concern. However, the available epidemiological data on these events remain scarce and uncertain, hindering a comprehensive understanding of the issue and the effective implementation of intervention strategies. After reviewing the definition of death in custody and international legislation regarding systematic approaches to forensic investigations, our study aimed to analyze the available data within the Italian context and compare it with international findings. We discussed the emerging critical points to identify potential solutions. Epidemiological data from registers, reports, and individual international studies were extracted and analyzed. A statistical comparison was conducted for data obtained from the records of the Italian Department of Penitentiary Administration for the period 1992-2021. A significant and moderate correlation emerged between the average incarcerated population per year and the number of deaths due to natural causes (r = 0.459, p = 0.005), while no significant correlation emerged between the first and the number of deaths due to suicide (r = 0.294, p = 0.058). In addition, no significant correlations emerged between the overcrowding index and the number of deaths due to natural causes or suicide (respectively, p = 0.703 and p = 0.056). Furthermore, a concerning discrepancy emerged between national and international data regarding the causes of death in custody, especially for suicides, along with a lack of in-depth and certain data. The relevance of the issue sets the necessity of a reflection on the need for changes at multiple levels. From a legislative perspective, it is proposed to establish a forensic investigation for all deaths in custody. Such a function could be assumed by specialized university centers, independent of other institutions, capable of ensuring training, research, high quality, and timely delivery of results. The implementation of protocols and procedures, along with the recording of easily accessible data, could ultimately ensure the safety of results and transparency, triggering a socially beneficial virtuous cycle.