Antibiotics and antibiotic resistance genes from animal manure applied to soil as fertilizer are now among the most concerned contaminants in soil. The widespread use of antibiotics in livestock might amplify the risk of developing antibiotic resistance, causing once treatable diseases to turn deadly. The World Health Organization declared antibiotic resistance as "one of the biggest threats to global health, food security, and development". The goal of this dissertation was to develop best manure management practices by understanding the behavior of manure-associated antibiotics in manure, water, and soil. In particular, my research focused on the effects of manure application methods, on-site manure treatment methods, manure application seasons, and manure-rainfall time gaps on antibiotic surface runoff losses, antibiotic distribution and movement in soil, antibiotic dissipation in soil, and development of antibiotic resistance. Rainfall simulation field-scale and soil incubation lab studies were combined to find the best manure management practices. My research has shown for the first time that using the manure soil subsurface injection method, especially during spring application season due to moist soil, applying manure at least 3 days before a subsequent rainfall, and using composted manure, can significantly reduce the quantity of antibiotic loss with runoff from manure-applied fields to the surrounding environment. The majority of applied antibiotics remained in soil. All antibiotics showed a similar dissipation pattern with fastest kinetics during the first 14 d before slowing down. The effect of two manure application methods on antibiotic dissipation kinetics varied with different antibiotics. Although the half-life of tested antibiotics in soil was short (<21 days), some remained detectable even at 6 months after a single manure application. Results also showed that compared to the surface application, the subsurface injection slits acted as a "hot zone" with a higher amount of antibiotics, manure microbes, and antibiotic resistance. The results provide information for policy makers, manure managers, and farmers to develop better manure management practices that can use manure as fertilizer while minimizing the spread of antibiotics to surrounding water, soil, and plants.