The Barony of Meldrum was originally the territory of Auchineve and was granted to Philip de Phendarg in 1236 by the Abbot of Arbroath during the reign of the Scottish King Alexander II. It is Sir Philip de Fendarg, the son, who is believed to have first carried the title of Meldrum, which was then spelt Melgdrum. A translation from the Gaelic of Meall Druim is: the ridge on the hill, which is appropriate given that the house was built on the only rocky outcrop on the highest point of the land.

The original tower house was built around this time and forms the nucleus of all the later changes from the 17th, 19th and 20th Centuries which leave the house as it stands today. The Meldrum family became powerful and great landowners within the northeast of Scotland with properties including Drumoak and Fyvie Castle, which came into the family when Alexander Meldrum of Meldrum married the youngest daughter of Sir Henry Preston in 1433. Their son, George, was to become an Ambassador to the Court of King Henry VIII. William Meldrum, the last of the male line of the Meldrums, only had two daughters and, with the eldest married, it was Elizabeth, the youngest daughter, who was to inherit the estate of Meldrum, whilst Drumoak and Fyvie remained with other branches of the family.

Elizabeth's marriage to Sir William Seton brought the Seton family into ownership of the estate. William was the second son of Sir Alexander Seton, 1st Lord Gordon, and brother of Alexander Seton 1st Earl of Huntly, however, William and his younger brother Henry were both killed at the Battle of Brechin on 18th May 1452. Their older brother, Alexander jr. (the Master of Gordon) took the name of Gordon to become 1st Earl Huntly. The estate of Meldrum passed to Sir William Seton's son, and was then to remain in the Seton family for a further 7 generations.

It was the offspring of these Seton's that were to become Chancellors of Aberdeen, Chancellors of the St. Machar's Catherdral and of the University of Aberdeen, Chamberlain's to the Earl of Winton, the Earl's of Dunfermline and the Earl's of Huntly and progenitors of the Setons of Pittmedden, of Mounie, of Belhelvie and others as well as extend the Seton family lands throughout the north of Scotland.

The direct line at Meldrum ended with Sir Alexander Seton. His eldest son, also Alexander jr "fiar of Meldrum", pre-deceased him in 1590, leaving a daughter Elizabeth: Alexander jr. having been slain by James King of Barra, whereby representation of the line passed to Alexander senior's second son, John and then his third son William, respectively.  At the death of William, last Seton of Meldrum in 1635, the male-line representation passed to the line of John Seton of Lumphart and 1st of Mounie who's eldest son was William Seton of Mounie, Menie and Udny.  When the Menie/Udny line ultimately failed in the person of Robert Seton, son of Captain Robert Seton (Captain of Blackness Castle), representation of the line then passed to John Seton of Lumphart's second son, also called John Seton (of Menie and of Aquhorthies) who was Chamberlain to the Earls of Dunfermline at Fyvie Castle.  This line emigrated to Ulster, Ireland in 1699 and later established branches in Pennsylvania as well as in Nova Scotia - current Representative's of the House of Seton of Meldrum - spelt as Seeton.

In the termination of the direct male-line of the Seton's of Meldrum, it was a long-standing feud which brought about the line demise.  The Kings of Barra were long at feud with the Seton's of Meldrum, which feud might have been expected to come to a close towards the end of the 16th century when James King sold Barra to the Seton's.  But no; as late as 1615, Elizabeth Seton pursued at law James King "sumtyme of Barra' and others for being art and part in the slaughter of her father, Alexander, fiar of Meldrum, 'with schottis of hagbuttis and muscattis, commited upon the landis of Barra...' (the Braes of Bourtie).

Sir Alexander's second son, John Seton of Meldrum, succeeded to the Estate but died in 1619 with no offspring from his marriage to Lady Grisel Stewart, daughter of the Earl of Atholl, and so it was Sir Alexander Seton's 3rd son William who inherited Meldrum. However, as William's marriage to Anne Crighton of Fendraught was also childless, he bequeathed the Estate to his brothers' daughter Elizabeth in 1625 for her to inherit on his death, which occured in 1635.

William Seton was responsible for the addition of the stone staircase in 1625 thereby creating the new entrance at the top of the stairs after blocking in the original archway to the internal courtyard. Also, 1628 saw the addition of the original stable block including the central tower still prominent today with its feature of a stone-carved Royal Coat of Arms on the northeast face, so placed for the visit of King Charles I to Meldrum House that same year

The heiress of Meldrum, Elizabeth Seton, married John Urquhart of Craigfintray, known as the Tutor of Cromarty in 1610.  When she inherited Meldrum Estate in 1635 on William's death, she passed the estate to her son Patrick Urquhart (she was the last actual Seton of Meldrum).  The Meldrum Estate was then to remain in the Urquhart family until 1898.  It was during the Urquhart tenure in the late 17th and early 18th Centuries that the house was extended with the addition of two wings running parallel and eastwards, a large joining wall connected these wings to create a substantial courtyard mansion house to reflect the status of the family at that time. There are four paintings dated 1772/73 that show the house in this style and the size that it had become.  It was James Urquhart of Meldrum that commissioned Archibald Simpson to redesign the house in 1836 to remove the "air of neglect" that had become noticeable.

Simpson's design took 3 years to complete and provided a Jacobean style mansion house of symmetrical design in a large C shape, with grand Portico entrance and turreted pavilions to a total of 86 rooms. The last Urquhart Laird was Major Beauchamp Colclough Urquhart who was killed at the Battle of Attbara in the Sudan on Good Friday 8th April 1898. The estate then passed to his sister, Annie Isabella, who had married her first cousin Garden Alexander Duff of Hatton.

Their son, Colonel Garden Beauchamp Duff, was to become Laird of Hatton and Meldrum, and it was Lady Doris Duff who commissioned W.L. Duncan to redesign the house in 1934. This saw the removal of the turreted pavilion and a complete story of the main house to leave the L shaped house of today.