Introduction: Implementation of prevention and control measures for communicable diseases in border regions can be challenging and lead to inefficient attempts to control them. We describe evidences on the strengths, weaknesses, opportunities and challenges regarding implementation of health interventions for control, prevention and treatment of selected neglected tropical diseases (NTD), a group of transmissible diseases typically prevalent in tropical countries and vulnerable populations, in the tri-border between Brazil, Argentina, and Paraguay. Methodology: A systematic literature review of observational and experimental studies was conducted, using PubMed and Bireme databases. Eligibility criteria were location (tri-border area) and subject (health interventions). Results: Of a total of 595 references identified, 34 studies were included (18 pertaining to leishmaniasis, 11 to dengue, 2 to leprosy, 2 to soil-transmitted helminthiases and 1 to Chagas’ disease), with an inclusion rate of 6.4%. The main strengths were the similarity of health interventions between countries and easiness of mobility and communication flows. The main weaknesses were access to rural areas and discrepancies in the number of studies between countries. As for opportunities, we identified increased tourism, economic development and recent increasing research in this field. The main challenges were the absence of studies regarding other prevalent NTD in the region and movement of goods, animals and people across borders. Conclusions: Although epidemiological studies are still needed to better understand and assess the prevalence of NTD in the area, mainly in Paraguay, these findings can inform decision-makers and health managers to plan a common strategy to address NTD.