Aim: Both the arterial and venous systems independently predict mortality in septic shock, yet no bedside tools are able to integrate their assessment. Risk stratification becomes challenging when arterial parameters suggest favourable outcomes while venous parameters indicate poor prognosis, or vice versa. To address this gap, we developed the VTI-VeXUS index and conducted this proof-of-concept study to test its association with mortality. Methods: We conducted a prospective cohort study in two ICUs, enrolling adult patients with septic shock. We calculated the VTI-VeXUS index (VTI/[VeXUS+1]) from ultrasound measurements obtained within 24 h of ICU admission and stratified patients as having a high or low VTI-VeXUS index based on a cutoff of 11. We evaluated the primary outcome of mortality at 30 days using survival analysis. Results: We enrolled 62 patients. Patients with a low VTI-VeXUS index had higher rates of left ventricular dysfunction (32.3% vs. 3.2%, p = 0.006), right ventricular dysfunction (35.5% vs. 0.0%, p < 0.001), lower stroke volume (54.0 mL vs. 62.0 mL, p = 0.005), and increased 30-day mortality (adjusted HR: 3.86, 95% CI 1.23 to 12.14). Conclusions: In this exploratory proof-of-concept study, a low VTI-VeXUS index was associated with ventricular dysfunction and increased mortality. While limited by small sample size and univariate analysis, these findings suggest this novel integrated metric warrants validation in larger prospective studies.