The objective of this study was to educate on the moderating effects of age and computer knowledge on nurses’ acceptance of information systems (IS). The background theoretical framework used was the technology acceptance model (TAM), which has been widely favored by healthcare researchers. A relevant research model including TAM’s core constructs, i.e., perceived usefulness (PUSS) and ease of use (PEOU), age, and computer knowledge was used. Usable data was collected from 197 registered nurses (RNs) in Nova Scotia, Canada, in a cross-sectional survey. The partial least squares (PLS) technique of structural equation modeling was used for data analysis. The results of the hypothesized relationships show that computer knowledge has a positive moderating effect on the influences of PEOU and PUSS on nurses’ attitudes toward IS (ATTI); the demographic factor of age did not. PEOU and PUSS have direct positive influence on nurses’ ATTI, which in turn impacts their behavioral intentions to use IS (BEHI). Lastly, nurses’ self-reported IS use is positively influenced by BEHI. The study’s results drew the attention of practitioners and academics to the impacts of age and computer knowledge in the discourse of nurses’ IS acceptance in work environments.