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Due to the importance of entrepreneurship and innovation in the Pharmaceutical industry, the current study investigates the moderation role of Entrepreneurial Orientation (EO) on the influence of innovation on Pharmaceutical SMEs performance in Jordan. The current research was conducted on Jordanian pharmaceutical SMEs including manufacturers, distributors, and pharmacies with employee numbers of less than 100. The research design was quantitative, descriptive, causal, and cross-sectional held by an online questionnaire tool targeted all employees, managers, and Chief Executive Officers (CEOs) in pharmaceutical SMEs. Using the AMOS software, the Structural Equation Model (SEM) was adopted to analyze a sample of 162 surveys and examine the hypotheses. The outcome of this study indicated that the research model variables can explain 69.4 % of the variance of SMEs' performance. Additionally, it confirmed that innovation has a significant positive impact on pharmaceutical SMEs, and Entrepreneurial Orientation moderates the influence of innovation on pharmaceutical SMEs' Performance. Furthermore, current research findings contribute to extending existing relevant knowledge about the innovation impact and moderating role of Entrepreneurial Orientation on pharmaceutical SMEs' performance in Jordan and understanding the relationship between these variables to be of significant guidance to managing entrepreneurship in emerging economies. Further, the results show SMEs' methods and directions to follow during crises, such as COVID-19, to maintain business performance and sustainability. The current research paper contributes to the present literature since very limited studies investigated the innovation impact on SMEs' performance. Moreover, previous studies did not sufficiently analyze the impact of management, product, and process dimensions of innovation on SMEs' performance with the contribution of EO.