Lyme disease (LD) is the most common vector-borne disease in France. Since 2009, surveillance of the disease in mainland France has been conducted by the Sentinelles network, a network of general practitioners. In addition, surveillance of hospitalized LD cases in France has been established using data from the Medical Information Systems Program database. The objective of this study was to estimate the incidence and trends of hospitalized LD cases over the period 2005 to 2016 and to describe their clinical manifestations. On average, 799 cases of LD were hospitalized annually, with a peak observed during the summer. Annual hospital incidence rates ranged from 1.1 cases per 100,000 inhabitants in 2005 to 1.5 in 2011, with no significant trend. Significant interregional variations in incidence were observed, with a higher rate in regions with high incidence as estimated by the Sentinelles network. The age distribution was bimodal, with incidence peaks among 5- to 9-year-olds and 70- to 79-year-olds. Among hospitalized cases, the most common clinical manifestation of LB was neuroborreliosis (51%). Following a period of stable incidence (2009–2015), the increase in LB incidence observed by the Sentinelles network in 2016 was not observed in hospital settings. Prevention strategies, focused in particular on the age groups most at risk and regions with high incidence, must continue to promote preventive measures such as protection against tick bites, checking the body for ticks after exposure, and their prompt removal.