Objective: This study aims to characterise the phenomenon of depopulation in the rural environment from the point of view of the opportunities offered by technology-based rural entrepreneurship as a lever that promotes population fixation and the economic dynamisation of the most depressed territories subject to the economic and social imbalances generated by depopulation. Research Design & Methods: The research approach is based on the application of case studies as an empirical research technique. In particular, the strategy for the promotion of rural start-ups in CyL – the largest European region and one of the Spanish regions most affected by the negative consequences of depopulation – is analysed. Findings: Empirical evidence has shown that economic conditions have impacted the extent and duration of migration flows from rural areas to a more industrialised urban environment. Thus, in recent decades, the spatial distribution of the population has taken shape characterised by strong concentrations in large cities as opposed to the dispersion and low density of the population in large areas of the territory. Implications / Recommendations: The promotion of rural entrepreneurship through the development of specific actions to encourage the creation of start-up companies could be a solution to the demographic challenge. Contribution / Value Added: The creation of a regional entrepreneurial ecosystem has been possible owing to the financing, growth, scaling, and business internationalisation programmes promoted by the regional government.