Agricultural expansion is a complex land use change phenomenon with deep environmental and socio-economic consequences, especially across tropical countries where most of this expansion is occurring. Here we use scenario and network analysis combined with sustainability assessment to understand the drivers of landscape change and their effects on sustainable development in Colombia’s rural areas, using the Central Magdalena region as a case study, and ultimately informing strategies to reconcile agricultural expansion with biodiversity conservation and rural development. Using this approach we investigated three environmental and agricultural policy scenarios: the Business as Usual scenario, enforcing a stronger regulatory framework, and adopting incentives. Our analysis show that the Business as Usual scenario is not supported by stakeholders and negatively affects most sustainability objectives with the predominant agricultural sectors in the region (cattle ranching and oil palm) not improving social inequality, and threatening biodiversity, natural resources, and food security. Both alternative scenarios improve overall sustainability, including biodiversity. Therefore to reconcile agricultural expansion, biodiversity and sustainable development, it is important to adopt a stronger regulatory and enforcement framework at different administrative levels, as well as incentive schemes focusing on small holders. Our study also shows that history cannot be ignored when thinking about the future and sustainability especially in areas with legacies of strong inequalities caused by armed conflict. Finally, we suggest that combining scenario analysis, network analysis, and sustainability assessment is a useful methodology for studying land use changes holistically, exploring complex systems at different scales, and informing locally-relevant strategies and recommendations, ultimately enabling science to be proactive.