Poultry litter (PL), a nutrient-rich byproduct of poultry production, offers significant agronomic value and supports sustainable agriculture. However, untreated PL can introduce microbiological hazards, including human pathogens and antibiotic resistance genes (ARGs). This chapter reviews treatment methods—such as composting, heat drying, pelletization, and chemical amendments—that mitigate these risks while enhancing soil health. We assess the effectiveness of these treatments in reducing pathogen transmission and their influence on soil microbial diversity and function under varying environmental conditions. The role of microbial inoculants, particularly competitive exclusion organisms, is also explored as a strategy to restore soil microbiota. Drawing on published studies, we identify microbial risks, highlight knowledge gaps, and propose strategies to optimize PL treatment for improved food safety and sustainable soil management.