The modern Nile delta developed in the Middle and Late Holocene, and at its most northern-central point is situated at the Burullus Lagoon, which is environmentally diverse, including salt marshes, mudflats, and sand plains, and separated from a sea by a sand barrier overtopped with high sand dunes. The lagoon has been fed since the Middle Holocene by the Sebennitic branch of the Nile and marine intrusions through the Bughaz inlet. A sediment core (BO-1) was collected at the northeastern shore of the lagoon and sampled at centennial scale resolution in order to reconstruct the development of the lagoon. The results show that an initial and limited lagoon had developed at the end of the Early Holocene, but after a dry period ca. 7.2 cal ka BP it has been progressively transformed into a marshy area, with occasional inflows of sea water. Lower water level and higher salinity of the Burullus Lagoon at 6.0–5.5 and 4.8–4.2 cal ka BP reflected droughts in the Nile catchment. Thereafter, the river reactivated in the Burullus Lagoon area, and since 2.8 cal ka BP was accompanied by occasional inflows of sea water. Since ca. 0.8 cal ka BP, increased fluvial activity occurred in this part of the Nile delta, which terminated after construction of the Aswan dams in the twentieth century.