Objective: Although nurses comprise the largest group of health professionals and electronic health record (EHR) user base, it is unclear how EHR use has affected nurse well-being. This systematic review assesses the multivariable (ie, organizational, nurse, and health information technology [IT]) factors associated with EHR-related nurse well-being and identifies potential improvements recommended by frontline nurses. Materials and Methods: We searched MEDLINE, Embase, CINAHL, PsycINFO, ProQuest, and Web of Science for literature reporting on EHR use, nurses, and well-being. A quality appraisal was conducted using a previously developed tool. Results: Of 4583 articles, 12 met inclusion criteria. Two-thirds of the studies were deemed to have a moderate or low risk of bias. Overall, the studies primarily focused on nurse-and IT-level factors, with 1 study examining organizational characteristics. That study found worse nurse well-being was associated with EHRs compared with paper charts. Studies on nurse-level factors suggest that personal digital literacy is one modifiable factor to improving well-being. Additionally, EHRs with integrated displays were associated with improved well-being. Recommendations for improving EHRs suggested IT-, organization-, and policy-level solutions to address the complex nature of EHR-related nurse well-being. Conclusions: The overarching finding from this synthesis reveals a critical need for multifaceted interventions that better organize, manage, and display information for clinicians to facilitate decision making. Our study also suggests that nurses have valuable insight into ways to reduce EHR-related burden. Future research is needed to test multicomponent interventions that address these complex factors and use participatory approaches to engage nurses in intervention development.