Human settlement development is intricately linked to production and life, and development quality is a partial indicator of the local community’s social, economic, cultural, and environmental progress. Furthermore, the human settlements’ vulnerability affects their sustainable development potential. Due to the “One Belt, One Road” initiative and land and sea corridor development in southwestern China, the Beibu Gulf coast in Guangxi is the sole waterway bridgehead used by China for opening trade with ASEAN. By examining the region’s human settlements and its potential for sustainable development, we established a benchmark for the region’s seaward economy and human settlements to achieve synergistic progress, as well as to enhance regional integration. Based on the systematic evaluation of the quality of human settlements along the Beibu Gulf coast in Guangxi, the vulnerability assessment model of human settlement was adopted to analyse the vulnerability and spatial–temporal patterns of nearby human settlements in 2010–2019, while the multiple linear regression model was used to explore their influencing factors. Our findings indicate that the quality of human settlements in the study area has experienced three distinct stages. In the early stage (2010–2012), we noted an overall year-on-year increase in settlement quality. However, in the middle stage (2013–2016), Fangchenggang and Beihai experienced a decline followed by an increase, while Qinzhou demonstrated a steady growth in settlement quality. Qinzhou continued to experience growth, albeit at a slower rate, while Fangchenggang’s rate of increase surpassed that of Beihai. The human settlements’ high-quality centre shifted between Qinzhou and Fangchenggang in the late stage (2017–2019). Additionally, in recent years, the settlements’ high-quality centre has shifted towards the western part of the region. The habitat’s sensitivity has grown slowly, as has the responsiveness index, but the vulnerability index continues to decline, and it is characterised by a spatial differentiation ranging from low to high values in a centre–east–west direction. The region’s human settlement quality is primarily influenced by economic development. The region’s habitat vulnerability is primarily caused by responsibility, and the primary factors affecting responsibility are regional imbalances in social service development, the population’s welfare, and employment and infrastructure.