Historically, leishmaniasis in Italy was constrained to areas with Mediterranean climate. In the last 20 years, sand fly vectors (Phlebotomus perniciosus), cases of canine leishmaniasis (CanL) and cases of human visceral leishmaniasis (VL) have been observed in Northern Italian regions, traditionally classified as cold areas unsuitable for sand fly survival. We aim to evaluate through a One-Health approach the risk of endemic transmission of Leishmania infantum in the Piedmont Region, Northern Italy. We collected environmental, entomological, animal, and human data. We applied a geostatistical binomial model to map the probability of P. perniciosus presence in the study area, using selected environmental parameters as predictors. We evaluated the spatial relationship between the probability of P. perniciosus presence and the geographical distribution of CanL and VL cases observed between 1999 and 2013. Between 1999 and 2003, 142 sampling sets (17%) out of 839 resulted positive for P. perniciosus. Elevation, degree of slope, normalized difference vegetation index (NDVI) and summer temperatures were associated with positive sampling sets. During the study period, 164 (13.6%) of Piedmont municipalities reported at least one autochthonous case of CanL, while 89 VL cases were observed in 54 municipalities (4.5%). We observed an association between municipalities affected by autochthonous CanL cases and the estimated probability of P. perniciosus presence (Odds Ratio for 10% increase of probability: 2.66; 95% confidence intervals (CI): 2.16–3.37). We found that human VL incident cases were positively associated with the probability of the municipality of residence of being endemic for CanL (Incidence Rate Ratio for 10% increase of probability: 1.49; 95% CI 1.02–2.16). Using a One-Health approach, we quantified the spatial association between the distribution of P. perniciosus, municipalities endemic for CanL and incident cases of human VL, suggesting that the disease has become endemic in the Piedmont region.