The growth of small and medium enterprises (SMEs) is an important prerequisite for the economic development of the country because it creates the lion’s share of jobs in developed economies and is an engine for innovations. SMEs usually do not have significant resources and are affected by changes in the external environment. In recent years, in Ukraine, a transit economy, small and micro-enterprises have been increasingly important in the economic processes. This article examines the effect of macroeconomic factors on the development of small and micro-businesses in Ukraine’s regions, namely the size of the gross regional product, purchasing power of the households, the value of gross exports and imports, income from sales of large enterprises. Using official statistical data, we created a panel-like dataset covering all regions of Ukraine for 2015-2019. We performed longitudinal modeling with fixed effects specification. We found a positive impact of a change in the total income and expenditures of households and a change in the foreign trade indicators and a negative impact of a change in gross regional product and a change in the economic performance of large enterprises on the number of small and micro-enterprises in the region.