The study evaluated individual and setting-specific factors that moderate clinicians’ perception regarding use of clinical decision support systems (CDSS) for antibiotic management. A cross-sectional online survey examined clinicians’ perceptions about CDSS implementation for antibiotic management in Australia. Multivariable logistic regression determined the association between drivers of CDSS adoption and different moderators. Clinical experience, CDSS use and care setting were important predictors of clinicians’ perception concerning CDSS adoption. Compared to nonusers, CDSS users were less likely to lack confidence in CDSS (OR = 0.63, 95%, CI = 0.32, 0.94) and consider it a threat to professional autonomy (OR = 0.47, 95%, CI = 0.08, 0.83). Conversely, there was higher likelihood in experienced clinicians (>20 years) to distrust CDSS (OR = 1.58, 95%, CI = 1.08, 2.23) due to fear of comprising their clinical judgement (OR = 1.68, 95%, CI = 1.27, 2.85). In primary care, clinicians were more likely to perceive time constraints (OR = 1.96, 95%, CI = 1.04, 3.70) and patient preference (OR = 1.84, 95%, CI = 1.19, 2.78) as barriers to CDSS adoption for antibiotic prescribing. Our findings provide differentiated understanding of the CDSS implementation landscape by identifying different individual, organisational and system-level factors that influence system adoption. The individual and setting characteristics can help understand the variability in CDSS adoption for antibiotic management in different clinicians.