As large areas of the Mississippi River Delta (MRD) of the USA disappear into the sea, present-day communities and cultural resources are lost. While the land loss may be readily quantified, describing the impact of cultural losses is less straightforward because cultural elements are frequently less tangible and difficult to map, identify, and categorize. The elision of cultural components of landscapes and ecosystems is evident in restoration practices and policies, although numerous scholars have identified the interlinked processes of culture and ecology as critical to rebuilding healthy and resilient environments. We define and measure cultural-ecosystem resilience (CER) in the Mississippi River Delta through analyses of Indigenous oral histories, mound-building practices and settlement patterns, and the persistence and reuse of archaeological sites. CER describes a system containing resilient properties embedded in human-natural settings including river deltas that may manifest in oral cultural traditions, architecture, and the selection of habitable environments. Our interdisciplinary approach demonstrates the role of human-modified landscapes in generating resilience for past and present coastal communities and highlights the importance of consulting records of historic and modern Indigenous traditions in shaping sustainable landscape-management strategies. Results show that archaeological earthen and shell mounds made by Native American Gulf Coast and MRD communities have been persistent features that endured for centuries and are sited in regions of high multicultural value within the dynamic delta. Yet, we document the rapid 20th-century loss of mounds due to coastal erosion, industry, and other human land-use practices. Present-day and future coastal land loss endangers what remains of these keystone features and thus lowers the resilience of modern Mississippi River Delta communities.