This paper documents the Late-Holocene environmental changes and human presence in the northern Danube delta using a multidisciplinary approach that combines geoscientific data with archaeological findings, historical texts, and maps. It follows the formation and progression of the Chilia distributary and the reconfiguration of socioeconomic activities. Sedimentary facies identified on five new cores by changes in texture properties, magnetic susceptibility, geochemistry, and macro- and microfauna composition together with the newly obtained chronology constrain the complex evolution of the Chilia branch as filling in a long-lasting bay and then of a giant lagoon (Thiagola) which covered most of the northern delta since the Old Danube lobe inception (ca. 7500 yrs BP) till modern Chilia development. It initiated during the Greek Antiquity (ca. 2500 yrs ar BP) at the delta apex, while in Roman times (ca. 1800 yrs BP) it pursued its slow flowing into the vast Thiagola Lagoon. The most dramatic transformations occurred in the last 800 years when the river passed east of the Chilia promontory, rapidly went through the present-day Matița-Merhei basin (several decades), and created its first open-sea outlet. Solid discharge increased in two distinct periods, once in the Middle Ages (ca. 750 yrs BP) and then in the Modern Period (ca. 150 yrs BP) due to human-induced land-use changes in the Danube watershed. The chronology of the cultural remains on the pre-deltaic Chilia promontory and the multiproxy analysis of a sediment core retrieved nearby downstream suggest the terrestrial connection of the island with the mainland in ancient times. The hitherto contended issue of the old Thiagola Lagoon and its location are redefined here, as are the original identifications of ancient and medieval toponyms and hydronyms, especially for Chilia-Licostomo, Byzantine, Genoese, Moldavian, Ottoman, and Russian trading point of great importance in the political and economic history of the Black Sea and neighboring regions.