The natural stone sector is an important driver of the Spanish and Italian economies, which underwent internationalization after the financial crisis of 2008 as part of a survival and development strategy. This article aims to study the financial and economic profitability of this sector in the two leading European production countries, as well as its determinants. For this purpose, the economic-financial data of a sample composed of 453 companies (203 Spanish and 250 Italian) from 2015–2019 were analyzed using the multiple linear regression methodology. To address the problems of possible endogeneity and omission of variables in the model, the dependent variable was used as a regressor with one and two lags, and panel data with fixed effects were considered after performing the Hausman test. The results show significant differences between the two countries, with higher profitability in Italy. Company size, company growth (measured as the change in assets), and the variation in the country’s GDP all positively affected profitability. At the same time, the level of indebtedness showed a negative relationship. The country’s inflation rate and gender diversity in top management were shown to be non-relevant variables. The research conducted indicates that, to increase profitability, Spanish and Italian companies in the natural stone sector should undergo mergers in order to grow in size, increase efficiency in the use of assets, reduce their dependence on external financing, and promote equity capital. In addition, Italian companies should reduce the average period of payment to suppliers to lower deferral costs, and boost exports to become less dependent on the country’s domestic economy.