In Italy, human cases of West Nile virus (WNV) infection have been recorded since 2008, and seasonal outbreaks have occurred almost annually. In this study, we summarize available evidences on the epidemiology of WNV and West Nile neuro-invasive disease (WNND) in humans reported between 2012 and 2020. In total, 1145 WNV infection cases were diagnosed; of them 487 (42.5%) had WNND. A significant circulation of the pathogen was suggested by studies on blood donors, with annual incidence rates ranging from 1.353 (95% confidence intervals (95% CI) 0.279-3.953) to 19.069 cases per 100,000 specimens (95% CI 13.494-26.174). The annual incidence rates of WNND increased during the study period from 0.047 cases per 100,000 (95% CI 0.031-0.068) in 2012, to 0.074 cases per 100,000 (95% CI 0.054-0.099) in 2020, peaking to 0.377 cases per 100,000 (95% CI 0.330-0.429) in 2018. There were 60 deaths. Cases of WNND were clustered in Northern Italy, particularly in the Po River Valley, during the months of August (56.7%) and September (27.5%). Higher risk for WNND was reported in subjects of male sex (risk ratio (RR) 1.545, 95% CI 1.392-1.673 compared to females), and in older age groups (RR 24.46, 95% CI 15.61-38.32 for 65-74 y.o.; RR 43.7, 95% CI 28.33-67.41 for subjects older than 75 years), while main effectors were identified in average air temperatures (incidence rate ratio (IRR) 1.3219, 95% CI 1.0053-1.7383), population density (IRR 1.0004, 95% CI 1.0001-1.0008), and occurrence of cases in the nearby provinces (IRR 1.0442, 95% CI 1.0340-1.0545). In summary, an enhanced surveillance is vital for the early detection of human cases and the prompt implementation of response measures.