Before the Plantation of Ulster in the early 1600s, the land at Prehen was held in freehold by Captain Manus O'Cahan. The plantation transferred it to the Goldsmiths' Company of London, who in turn granted the main charter in 1664 to Alexander Tomkins. He built the first proper house and made the place habitable. Three generations later, in 1738, his great-granddaughter Honoria Tomkins married Andrew Knox of Rathmullan and Moneymore, a great-great-grandson of the Andrew Knox who had arrived from Scotland in 1609 as Bishop of the Isles, charged with planting Protestantism in Donegal. By 1740 Andrew Knox owned Prehen as his third property. He built Prehen House, the Georgian mansion still standing today, and his family would live there for 170 years.

John MacNaghten arrived at Prehen as a friend of the family. He courted Andrew Knox's only daughter Mary Ann and, by some account, tricked her into a marriage ceremony when she was sixteen and he was thirty-four. Knox refused to recognise the union, refused to release her dowry of £5,000, and had a court declare the marriage void on the grounds of her age. MacNaghten swore revenge. For two years he stalked Mary Ann around the country, looking for an opportunity to abduct her. He found it in November 1761, when the Knox family travelled by coach to Dublin for the opening of Parliament - Andrew was MP for County Donegal. MacNaghten and his accomplices ambushed the coach at Cloghcor Wood near Strabane. In the firefight that followed he aimed at Andrew Knox, who was sitting next to his daughter, and accidentally shot Mary Ann instead. She died four hours later. MacNaghten, wounded, was found hiding in a nearby hay-loft. The court at Lifford sentenced him to hang. The rest is the rope. Mary Ann's mother retired to her room every year on the anniversary of her daughter's death and refused to come out until the next day - a private grief that lasted until her son married a girl from Strokestown who became, by all accounts, a second daughter to her.

The Knox family held Prehen until 1910, when Colonel George Knox died and the estate passed to his grandson, Baron George Von Scheffler, husband of Baroness Kathryn Von Gahan. Von Scheffler was German-born and an officer in the Prussian Guard. When the Great War began in 1914 he was forced to leave Prehen as an enemy of the British state. The estate was confiscated as enemy property and liquidated by public auction after the war, under the Trading with the Enemy Amendment Act 1914. A Knox lineage of 170 years ended because of a European war. The house then changed hands several times. A timber merchant cut down many of Prehen's fine old trees to build newer housing. In the 1960s a small private estate, Prehen Park, was developed on the borders of the old grounds. Two more small developments, Dunwood and Stoneywood, followed.

Two other Prehen stories sit in the local memory. In 1689, during the Siege of Derry, more than ten thousand Jacobite troops were entrenched in positions around Prehen, watching the city across the river. A French officer was riding at the head of his troop near the bank when a marksman on the opposite shore - William Houston from Newtoncunningham in Donegal - shot him dead at long range with a fowling piece. What made the shot legendary is that Houston had only one eye. The story has the flavour of folklore polished by decades of retelling, but it sits in the same landscape as the siege itself, and the Foyle is not so wide that a good shooter could not have managed it. Prehen Wood was also a favourite ambush spot for highwaymen, who used its cover to attack coaches on the main road. The Derry-Dublin road through the area was finally made in 1795. Prehen House was acquired in 1971 by the Peck family, formerly of Rathbeale Hall, who restored it and opened it to the public in September 2004. The Peck family connection runs deeper than restoration: Julian Peck's mother, Lady Winifred Peck, was a sister of Dilly Knox, who ran the code-breaking at Bletchley Park.