Background Patients with acute stroke at non‐ or primary stroke centers (PSCs) are transferred to comprehensive stroke centers for advanced treatments that reduce disability but experience significant delays in treatment and increased adjusted mortality. This study reports the results of a proactive, systematic, risk assessment of the door‐in‐door‐out process and its application to solution design. Methods and Results A learning collaborative (clinicians, patients, and caregivers) at 2 PSCs and 3 comprehensive stroke centers in Chicago, Illinois participated in a failure modes, effects, and criticality analysis to identify steps in the process; failures of each step, underlying causes; and to characterize each failure’s frequency, impact, and safeguards using standardized scores to calculate risk priority and criticality numbers for ranking. Targets for solution design were selected among the highest‐ranked failures. The failure modes, effects, and criticality analysis process map and risk table were completed during in‐person and virtual sessions. Failure to detect severe stroke/large‐vessel occlusion on arrival at the PSC is the highest‐ranked failure and can lead to a 45‐minute door‐in‐door‐out delay caused by failure to obtain a head computed tomography and computed tomography angiogram together. Lower risk failures include communication problems and delays within the PSC team and across the PSC comprehensive stroke center and paramedic teams. Seven solution prototypes were iteratively designed and address 4 of the 10 highest‐ranked failures. Conclusions The failure modes, effects, and criticality analysis identified and characterized previously unrecognized failures of the door‐in‐door‐out process. Use of a risk‐informed approach for solution design is novel for stroke and should mitigate or eliminate the failures.