Background: Clinical pathways (CPs) can improve patient outcomes but can be complex to implement. Technologies, such as clinical decision support (CDS) tools, can facilitate their use, but require end-user testing in clinical settings. Objective: This study applied the Technology Acceptance Model to evaluate the individual, organizational, and technological contexts impacting application of a portal to facilitate a CP for anxiety and depression (the ADAPT Portal) in a metropolitan cancer service. The ADAPT Portal triggers patient screening on patient reported outcomes, alerts staff to high scores, recommends evidence-based management, and triggers review and rescreening at set intervals. Methods: Quantitative and qualitative data on portal activity, data accuracy, and health service staff perspectives were collected. Quantitative data were analyzed descriptively, and thematic analysis was applied to qualitative data. Results: Overall, 15 (100% of those invited) health service staff agreed to be interviewed. During the pilot, 73 users (36 health service staff members and 37 patients) were registered on the ADAPT Portal. Of the 37 patients registered, 16 (43%) completed screening at least once, with seven screening positive and triaged appropriately. In total, 34 support requests were lodged, resulting in 17 portal enhancements (technical issues). Health service staff considered the ADAPT Portal easy to use and useful; however, some deemed it unnecessary or burdensome (individual issues), particularly in a busy cancer service (organizational issues). Conclusions: User testing of a CDS to facilitate screening and assessment of anxiety and depression in cancer patients highlighted some technological issues in implementing the ADAPT CDS, resulting in 17 enhancements. Our results highlight the importance of obtaining health service staff feedback when piloting specialized CDS tools and addressing contextual factors when implementing them.