Weed management is a crucial issue in agriculture, resulting in environmental in-field and off-field impacts. Within Agriculture 4.0, adoption of UASs combined with spatially explicit approaches may drastically reduce doses of herbicides, increasing sustainability in weed management. However, Agriculture 4.0 technologies are barely adopted in small-medium size farms. Recently, small and low-cost UASs, together with open-source software packages, may represent a low-cost spatially explicit system to map weed distribution in crop fields. The general aim is to map weed distribution by a low-cost UASs and a replicable workflow, completely based on open GIS software and algorithms: OpenDroneMap, QGIS, SAGA and OpenCV classification algorithms. Specific objectives are: (i) testing a low-cost UAS for weed mapping; (ii) assessing open-source packages for semi-automatic weed classification; (iii) performing a sustainable management scenario by prescription maps. Results showed high performances along the whole process: in orthomosaic generation at very high spatial resolution (0.01 m/pixel), in testing weed detection (Matthews Correlation Coefficient: 0.67–0.74), and in the production of prescription maps, reducing herbicide treatment to only 3.47% of the entire field. This study reveals the feasibility of low-cost UASs combined with open-source software, enabling a spatially explicit approach for weed management in small-medium size farmlands.