Posidonia oceanica meadows are Mediterranean coastal habitats of great conservation importance. This study is focused on a meadow located at Tremiti Islands Marine Protected Area (Adriatic Sea, Italy), which was monitored in 2003, 2015, and 2020 to evaluate its health state over time in relation to coastal human activities, which have been highly affecting this MPA for the last 20 years. To assess any change in the physiognomy of the meadow, rhizome density, percentage coverage, and lower limit progressions and/or regression over time were evaluated by scuba diving, while the distribution and extension of the meadow were assessed through habitat mapping using a side-scan sonar. Moreover, phenological and lepidochronological analyses were performed on the collected rhizomes to assess the leaf area index (LAI, m2m−2) and the rhizome age (lepidochronological years). Our study showed a general deterioration of P. oceanica meadow from 2003 to 2020, with a significant reduction of its absolute and relative rhizome density and LAI at almost all sampling stations, absence of renovation of the meadow, and lower limit regression and overall worsening of the main conservation status indicators. However, appropriate management actions, such as the establishment of mooring buoy fields, supported the improvement of the P. oceanica status at the local scale with a significant increase in density and LAI and the presence of active stolonization processes, suggesting that mitigation actions can play a crucial role in the conservation of this habitat. On the contrary, local anthropogenic impacts, especially anchoring and coastal development, markedly affect the resilience of P. oceanica meadows to global stressors, such as climate change.