An assessment on the fluctuations in abundance of the striped venus clam (Chamelea gallina) in the southern Adriatic Sea (Central Mediterranean Sea), and the northern Gargano area, has been conducted through both historical information and recent data from monitoring surveys during the period 1997–2019. Production trends, conditions of the commercial stock biomass, and depth distribution pattern of juveniles and commercial sizes were analysed testing temporal differences. Moreover, the exploitation of the clam beds and recruitment events were investigated in 2018–2019. Changes in abundance were analysed using non-parametric tests for both juvenile (length class, LC < 22 mm) and commercial (LC ≥ 22 mm) fractions. Hydrodynamic changes, temperature and salinity variations were explored using a 3D hydrodynamic numerical model (MIKE 3 FM-HD) and statistical analysis, as well as changes in benthic assemblages impacted by hydraulic dredges were investigated through PERMANOVA and other multivariate analysis.The results showed a temporal decline of production and biomass of C. gallina during the 1997–2019 period, and a regression of the depth limit in the clams’ distribution towards shallower waters. A significant reduction in juveniles was observed during 2018–2019 with a very limited recruitment. The fishing exploitation showed high impacts on the commercial stock and benthic assemblages in the summer of 2018. Overall, water currents were predominantly directed offshore in 2018, during the C. gallina spawning period. This could affect the larval dispersal and settlement on unsuitable bottoms. Anomalies in temperature (high peaks in August 2018, > 28 °C) and salinity (low values in spring 2018, < 37 PSU) could have induced stress and mortality events on the entire clam bed in the study area. This first study highlights the need to integrate environmental information in the assessment of commercial stocks of clams in the Adriatic Sea, to better understand climate change effects on the fluctuations and to support effective ecosystem-based fishery management.