A university-focused alliance portfolio is a manifestation of industry–university–research cooperation and has become an important path to realize original innovation in science and technology. Unlike traditional technological innovation, original innovation particularly emphasizes new ideas and research areas never covered before. This paper integrates resource-based theory, alliance portfolio theory, and innovation theory, and aims to scientifically establish an evaluation index system of original innovation performance from the three dimensions of initiate research, technology breakthrough, and research breakthrough. The work explores how a university can select partners to realize collaborative innovation in the context of inter-organizational scientific research cooperation with multiple innovation subjects for nationwide research institutes and universities in mainland China. The empirical results show that resource complementarity has a significant positive effect on innovation performance. Three typical universities in the “2011 project” are selected as post-interview cases for enriching empirical evidence. This study contributes to original innovation literature by introducing the concept of resource complementarity in a university-focused alliance portfolio, and further provides implications for original and science-driven innovation studies and suggests directions for university and research institutes.