At the end of the 1990s, the Northwestern uplands of Cambodia were one of the last forest frontiers of the country. In a region that was the last Khmer Rouge stronghold, the opening of former conflict zones after a peace agreement initiated a vast movement of agricultural colonization. This movement was economically triggered by high market demand for agricultural commodities such as maize and cassava and fueled by a massive flow of spontaneous in-migration of land-poor farmers from lowland regions around the entire country. Focused on four upland districts along a pioneer front of Northwestern Cambodia, we analyzed historical trajectories of land use/cover changes using a chronological series of Landsat data from 1976 to 2016. We identified key drivers of deforestation using demographic data and qualitative information from local actors and other relevant stakeholders. We found a 65 percent forest cover loss due to conversion by smallholders into agricultural land for maize and cassava cultivation over a period of 15 years. The underlying mechanisms of land use change were further investigated to understand the diversity of individual farm trajectories and decision-making processes in relation to land conversion. These elements of diagnosis are essential to engage farming communities in innovative land use systems and to develop sustainable alternatives to boom crops that have led to the current situation of land degradation and economic instability.