Background: The American Optometric Association defines computer vision syndrome (CVS), also known as digital eye strain, as “a group of eye- and vision-related problems that result from prolonged computer, tablet, e-reader and cell phone use”. We aimed to create a well-structured, valid, and reliable questionnaire to determine the prevalence of CVS, and to analyze the visual, ocular surface, and extraocular sequelae of CVS using a novel and smart self-assessment questionnaire. Methods: This multicenter, observational, cross-sectional, descriptive, survey-based, online study included 6853 complete online responses of medical students from 15 universities. All participants responded to the updated, online, fourth version of the CVS questionnaire (CVS-F4), which has high validity and reliability. CVS was diagnosed according to five basic diagnostic criteria (5DC) derived from the CVS-F4. Respondents who fulfilled the 5DC were considered CVS cases. The 5DC were then converted into a novel five-question self-assessment questionnaire designated as the CVS-Smart. Results: Of 10000 invited medical students, 8006 responded to the CVS-F4 survey (80% response rate), while 6853 of the 8006 respondents provided complete online responses (85.6% completion rate). The overall CVS prevalence was 58.78% (n = 4028) among the study respondents; CVS prevalence was higher among women (65.87%) than among men (48.06%). Within the CVS group, the most common visual, ocular surface, and extraocular complaints were eye strain, dry eye, and neck/shoulder/back pain in 74.50% (n = 3001), 58.27% (n = 2347), and 80.52% (n = 3244) of CVS cases, respectively. Notably, 75.92% (3058/4028) of CVS cases were involved in the Mandated Computer System Use Program. Multivariate logistic regression analysis revealed that the two most statistically significant diagnostic criteria of the 5DC were greater than or equal to 2 symptoms/attacks per month over the last 12 months (odds ratio [OR] = 204177.2; P <0.0001) and symptoms/attacks associated with screen use (OR = 16047.34; P <0.0001). The CVS-Smart demonstrated a Cronbach’s alpha reliability coefficient of 0.860, Guttman split-half coefficient of 0.805, with perfect content and construct validity. A CVS-Smart score of 7–10 points indicated the presence of CVS. Conclusions: The visual, ocular surface, and extraocular diagnostic criteria for CVS constituted the basic components of CVS-Smart. CVS-Smart is a novel, valid, reliable, subjective instrument for determining CVS diagnosis and prevalence and may provide a tool for rapid periodic assessment and prognostication. Individuals with positive CVS-Smart results should consider modifying their lifestyles and screen styles and seeking the help of ophthalmologists and/or optometrists. Higher institutional authorities should consider revising the Mandated Computer System Use Program to avoid the long-term consequences of CVS among university students. Further research must compare CVS-Smart with other available metrics for CVS, such as the CVS questionnaire, to determine its test-retest reliability and to justify its widespread use.