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Simple Summary: A comprehensive assessment of the life history parameters of the invasive Atlantic blue crab Callinectes sapidus in the Lesina Lagoon (Adriatic Sea, SE Italy) in terms of abundance, sex ratio, size–frequency distribution, morphological maturation, growth, and mortality was provided adopting a suite of analytical techniques. The results of the present study can provide a valuable knowledge basis for future comparative investigations on the fishery biology of C. sapidus in Mediterranean waters. The fishery biology of the invasive Atlantic blue crab Callinectes sapidus in the Mediterranean Sea outside the eastern sectors of the basin has been only recently investigated. Here we studied the population of C. sapidus in the Lesina Lagoon (Adriatic Sea, SE Italy). In total, 838 crabs were captured monthly between February 2021 and January 2022 using fyke nets. Abundances varied seasonally with catches per unit effort ranging between 0 and 1.76 crabs fyke nets−1 d−1 in winter and summer. Spatial abundances estimated in summer by a Carle–Strub procedure ranged between 0.06 and 0.64 crabs m−2. The sex ratio (♂/♀) was close to 1:1; males prevailed only in August and September; ovigerous females occurred from April to August. The males' size at morphological maturity was smaller than females (110.6–112.3 mm vs. 122.1–123.1 mm). Seasonal von Bertalanffy growth parameters indicated that, compared with males, females showed a shorter maximum lifespan (5 vs. 8 years), a higher growth coefficient K (0.6 vs. 0.4 y−1) and growth performance index Ф' (4.6 vs. 4.3), while maximum sizes CW∞ (237.8 vs. 232.6 mm) and seasonality indices C (0.62 vs. 0.57) were similar. Furthermore, females showed higher natural and fishing mortalities and exploitation rate. We discussed the results of the present study in the context of the available literature to provide a valuable basis for the implementation of standardized Mediterranean-scale management plans, matching exploitation of C. sapidus with sustainable conservation of coastal ecosystems. [ABSTRACT FROM AUTHOR]