Diabetes is one of the major co-morbidities contributing to the high global burden of tuberculosis (TB). The increased susceptibility of individuals with type 2 diabetes (T2D) to TB is multifactorial and may influence the efficacy of vaccines. This study was undertaken to determine the early immune responses that occur following infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG) in a diet-induced murine model of T2D. The phagocytic capabilities of alveolar (AM) and resident peritoneal macrophages (RPM) were assessed using ex vivo assays. Compared to macrophages from non-diabetic mice, macrophages from diabetic animals showed decreased BCG uptake and killing and inflammatory cytokine production (TNF-α, MCP-1, IL-6, IL-1β). In vivo susceptibility to BCG was determined following intravenous infection and diabetic mice showed a trend towards increased mortality, higher bacterial burden in the lung, liver and spleen and increased inflammatory lesions compared to controls. Differences between tissue cytokines were observed as early as one day post-infection and by days 14 and 35, lung and liver TNF-α and IFN-γ levels were decreased in diabetic mice compared to controls. These results suggest that early dysregulated immune responses may influence the susceptibility of T2D mice to BCG infection.