This socio-anthropological study investigates the relations between humans and rodents in an area adjacent to the Limpopo National Park in Mozambique. Designed as part of the larger researcher on mammarenaviruses, it explores the social dimensions of the rodent-human interface, considering its spatial and temporal variability. Its results contribute to our understanding of the socio-ecological context in which new pathogens or new routes of pathogen transmission could arise and potentially spread diseases. A vulnerability-based approach was used to assess human exposure, sensibility and capacity to adapt to rodents. This study revealed: (i) Local knowledge of the dynamic of rodent populations over the last few decades, with new invasive rodents displacing native species; (ii) the social-ecological factors thought to be behind this invasion: climate change, new infrastructure (e.g., construction of a dam), new agricultural practices (e.g., cultivation of sunflowers) and policies (human resettlement); (iii) the significant impact associated with new invasive rodents (e.g., crop losses, damage to belongings), the limited capacity for individual and collective interventions to mitigate damage, and the little concern shown for rodent-related diseases; (iv) women and girls' high vulnerability to potential rodent-borne diseases due to frequent direct and indirect contact with rodents in the domestic space; and (v) the added-value of using a vulnerability-based methodology, over the more commonly used Knowledge-Attitudes-Practices (KAP) methodology, to map the structural factors shaping the human-rodent interface and its dynamic. Our findings suggest that the vulnerability-based approach could offer an opportunity to better respond to the One Health ambition by integrating social dimensions of health and grasping the complexity of the social and material context in which new pathogens could emerge and spread.