As the magnitude, complexity, and urgency of many sustainability problems increase, there is a growing need for universities to contribute more effectively to problem solving. Drawing upon prior research on social-ecological systems, knowledge-action connections, and organizational innovation, we developed an integrated conceptual framework for strengthening the capacity of universities to help society understand and respond to a wide range of sustainability challenges. Based on experiences gained in creating the Senator George J. Mitchell Center for Sustainability Solutions (Mitchell Center), we tested this framework by evaluating the experiences of interdisciplinary research teams involved in place-based, solutions-oriented research projects at the scale of a single region (i.e., the state of Maine, USA). We employed a multiple-case-study approach examining the experiences of three interdisciplinary research teams working on tidal energy development, adaptation to climate change, and forest vulnerability to an invasive insect. Drawing upon documents, observations, interviews, and other data sources, three common patterns emerged across these cases that were associated with more effective problem-solving strategies. First, an emphasis on local places and short-term dynamics in social-ecological systems research provides more frequent opportunities for learning while doing. Second, iterative stakeholder engagement and inclusive forms of knowledge co-production can generate substantial returns on investment, especially when researchers are dedicated to a shared process of problem identification and they avoid framing solutions too narrowly. Although these practices are time consuming, they can be accelerated by leveraging existing stakeholder relationships. Third, efforts to mobilize interdisciplinary expertise and link knowledge with action are facilitated by an organizational culture that emphasizes mutual respect, adaptability, and solutions. Participation of faculty associated with interdisciplinary academic programs, solutions-oriented fields, and units with partnership-oriented missions hastens collaboration within teams and between teams and stakeholders. The Mitchell Center also created a risk-tolerant culture that encouraged organizational learning. Solutions-focused programs at other universities can potentially benefit from the lessons we learned.