Abstract: Objective: This study examined feasibility, acceptability, and preliminary clinical impact of Veterans Affairs Coordinated Anxiety Learning and Management- Substance (VA CALM-S), a computer-assisted, transdiagnostic cognitive behavioral intervention for co-occurring anxiety and substance use disorders (SUDs) among veterans. Methods: Veterans with co-occurring anxiety and SUDs were randomized to receive VA CALM-S (n = 14) or usual care (n = 12). Acceptability and feasibility were assessed via treatment completion rates and qualitative feedback. Changes in self-reported anxiety symptoms, substance use, and substance-related consequences were assessed at posttreatment. Results: Eighty-five percent of participants completed all VA CALM-S modules. Qualitative feedback indicated the intervention was well-received and helpful. Moderate-to-large effect sizes were observed for VA CALM-S in reducing anxiety symptoms (d = 0.64), substance use (d = 0.69), and substance-related consequences (d = 0.34). Relatively smaller effect sizes were observed for the usual care condition in anxiety symptoms (d = 0.24), substance use (d = 0.12), and substance-related consequences (d = −0.46). Conclusions: Findings support the feasibility and acceptability of VA CALM-S for veterans with co-occurring anxiety and SUDs.