This paper examines the creation of entrepreneurial opportunities under coupled technical and demand uncertainty within Science-Based Ventures (SBVs). Whereas opportunity creation theory emphasizes cognitive and discursive processes, we build on practice theory and pragmatism to explore how SBV opportunities also emerge through entrepreneurs’ evolving engagements with material artifacts. Through a longitudinal multiple-case study, we identify two patterns of material engagement: epistemic engagement, oriented toward knowledge creation, and pragmatic engagement, oriented toward practical use. We show how opportunity creation unfolds through interweaving cycles of epistemic and pragmatic engagement. By introducing material engagements as constitutive, we extend creation theory for SBVs and highlight the central role of materiality in shaping belief formation, opportunity objectification, stakeholder engagement, and the variation–selection–retention process.