Rural areas are particularly important for ensuring sustainability and smart development of a state as a whole. The present study reflects the quantitative and qualitative assessment of smart growth challenges in the region of Latgale (Latvia) at the level of 19 districts. Worked out within the framework of the Latvian National Research Programme EKOSOC-LV, the present study focuses on smart growth as a tool for risk prevention and the use of opportunities in regional development within the framework of the concept of smart specialization. The research aim is to estimate the risk factors that influence the formation of a smart territory and to analyse the interrelationship of quantitative indicators and expert opinions. By analysing the theoretical principles, the regional actors’ recommendations, taking into account the research group participants’ and regional experts’ findings, the authors characterize the processes and the risks of smart development, as well as make assumptions about the development of the desired situation. The significant risk in the development of Latgale region is the decline in its population. At the same time, the results of the research show that the population is the most important cornerstone of smart growth of the rural territories in Latgale region. Both the objective data processing (statistical analysis) and the subjective point of view (the results of the expert survey) highlight a number of significant risk factors for promoting smart regional space and the growth of knowledge-based economy: the insufficient development of the population’s economic activity particularly in the knowledge-based segment, and the small population size. The assessment of various challenges and risks in the regional development of Latvia, as well as the integrated application of quantitative and qualitative approaches allows for the elaboration of a comprehensive vision of the smart growth processes in Latgale region of Latvia. The quantitative assessment is based on the establishment and testing of the integrated index (Smart Development Index). The qualitative assessment is based on the regional experts’ opinions summarized by using the Analytic Hierarchy Process methodology. The research results have both scientific and practical applicability in promoting smart development in rural areas. First of all, the results of the study offer a possible methodological solution for the assessment of smart development. Secondly, the obtained scientific experience can be used for solving practical problems at the level of the districts of Latgale region.