The Brazilian Amazon is part of one of the largest river systems in the world, in which the transport of cargo and passengers is commonplace. However, several accidents still occur to passenger ships, causing fatalities. Transportation occurs commonly in remote regions, where there are transport inequalities, and emergency assistance is hard to find. This can affect sustainability in communities with considerable levels of economic and social vulnerability. More information is needed about accidents involving inland transport in the Amazon, to identify the threats to ships and propose strategies for accident prevention. This paper addresses the main problems that long-distance passenger ships face in the Brazilian Amazon, presenting an integrated framework towards accident prevention. First, the present situation is characterized in terms of ship description, spatial distribution, and regulations that are applicable. Next, possible causes of passenger ship accidents are discussed, including topics of concern that should be considered in the Amazon waterways. Finally, measures to help minimize passenger ship accidents are proposed, and the social relevance is discussed. It was found that accidents in the Amazon are due to a combination of human and environmental factors. Stakeholders should strengthen the technical and legal training of ship operators. The use of new technologies for navigational aid and necessary maintenance of ships is suggested. Marine accident prevention initiatives should consider local conditions, such as environmental preservation, cultural respect, and difficulties related to navigation through the complex riverine system of the Amazon region.