Background Nursing care for patients with delirium is very complex and stressful and is associated with considerable care strain for nurses. Delirium recognition is the first step to the prevention and management of delirium and reduction of strain of care. Education is one of the strategies for improving nurses’ delirium recognition ability. Objectives This study aimed to evaluate the effects of interactive E-learning on delirium recognition ability and delirium-related strain of care among critical care nurses. Methods This quasi-experimental study was conducted in 2019 using a two-group pretest-posttest design. Participants were 98 critical care nurses recruited through a census from two hospitals in Iran. They were non-randomly allocated to an intervention and a control group. Study intervention was an interactive E-learning program with four parts on delirium, its prevention, its treatment, and its diagnostic and screening procedures. The program was uploaded on a website and its link was provided to participants in the intervention group. Before and two months after the intervention, data were collected using the Strain of Care for Delirium Index and five case vignettes. For data analysis, the Chi-square, Fisher’s exact, independent-sample t, and paired-sample t tests were performed usingthe SPSS software (v. 16.0). Findings Groups did not significantly differ from each other regarding the pretest mean scores of delirium recognition ability and strain of care. After the intervention, the mean score of delirium recognition ability in the intervention group was significantly greater and the mean score of strain of care was significantly lower than the control group (P < 0.05). Conclusion Interactive E-learning is effective in significantly improving critical care nurses’ delirium recognition ability and reducing their strain of care. As nurses’ heavy workload and limited free time are among the main barriers to their participation in face-to-face educational programs, interactive E-learning can be used for in-service education.