Literature on regional entrepreneurship has tended to neglect inter-regional flows of human capital, and yet spatial mobility provide the nascent entrepreneurs with multi-location knowledge and networks to exploit entrepreneurial opportunities. The paper fills the gap by adopting an agent-environment interactionist perspective in the investigation on the interrelation between mobility and entrepreneurship. To be more specific, it deals with two underlying themes. First, the way through which the multi-location experiences and non-local knowledge equip the migrants with the pursuit of opportunity-driven entrepreneurship. Second, the distinctive relationship between the regional environment and opportunity-driven entrepreneurial motives for individuals with and without spatial mobility experiences. These themes are investigated with the China labor-force dynamics survey data, comparing the characteristics and drivers of entrepreneurial motives of the migrants and locals. The survey data presents clear evidence of a higher prevalence of opportunity-driven entrepreneurship in migrant entrepreneurs compared to their local counterparts. Furthermore, the ordered logit regression results demonstrate that spatial mobility experiences significantly promote the likelihood of entering into opportunity-based business. The regional environment exerts impacts on migrants and non-migrants’ entrepreneurial motives, yet in different ways. Local entrepreneurs are more influenced by the endogenous nature of firm ecology in the city, whereas migrant entrepreneurs start business pulled by both local demands and extra-local connectedness to greater market areas. Finally, the paper reflects upon possible implications for a more targeted and inclusive entrepreneurial policy, as well as the future areas of research.