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He was born about 1597, the son of Richard Mytton of Halston, Shropshire, by his wife Margaret Owen, daughter of Thomas Owen of Condover. Thomas Mytton's only sister Sarah Mytton married the Royalist Colonel and MP Sir Edward Acton, 1st Baronet.
On 10 April 1643 the Parliament associated Shropshire with Warwickshire and Staffordshire under the command of Basil Feilding, 2nd Earl of Denbigh, Mytton being named as one of the committee for Shropshire. On 11 September 1643 Sir Thomas Myddelton and Mytton together seized Wem, and established there the first parliamentary garrison in Shropshire. Mytton was made governor, and in October defeated Lord Capel's attempt to recapture the town. On 12 January 1644 he surprised the cavaliers at Ellesmere, capturing Sir Nicholas Byron, Sir Richard Willis, and a convoy of ammunition. On 23 June 1644 Mytton, in conjunction with Lord Denbigh, captured Oswestry, and succeeded in holding it against a royalist attempt at recapture. He was appointed Governor of Oswestry, and the newspapers were full of praise. On 22 February 1645 he took part in the capture of Shrewsbury, though the credit was disputed between Mytton and Lieutenant-Colonel Reinking.
On the passing of the self-denying ordinance Sir Thomas Myddelton, a sitting member of parliament, was obliged to lay down his commission, and Mytton succeeded to his post as commander-in-chief of the forces of the six counties of North Wales, 12 May 1645. He was also appointed High Sheriff of Shropshire, 30 September 1645. From this point he is frequently described as Major-General Mytton. He took part in the defeat of Sir William Vaughan near Denbigh on 1 November 1645, frustrating the royalist attempts to relieve Chester. Once Chester had fallen, Mytton went on to besiege the rest of the royalist garrisons in North Wales: Ruthin (12 April 1646), Carnarvon (5 June 1646), Beaumaris (14 June 1646), Conwy town and castle (9 August, 18 November 1646), Denbigh (26 October 1646), Holt Castle (13 January 1647), and Harlech Castle (15 March 1647) surrendered in turn to Mytton's forces. Parliament maintained Mytton as commander-in-chief in North Wales when the army was disbanded (8 April 1647), and appointed him vice-admiral of North Wales in place of Glyn (30 December 1647). He was also granted £5,000 out of the estates of royalist delinquents.
In the Second Civil War Mytton was again active on the parliamentary side, and recovered Anglesey from the royalists. The king's execution did not shake his adherence to the parliament, and in September 1651 he agreed to act as a member of the court-martial which sentenced James Stanley, 7th Earl of Derby to death. He represented Shropshire in the first Protectorate Parliament convened by Oliver Cromwell in 1654.
In 1629 Mytton married Margaret (or Magdalen) Napier, a daughter of Sir Robert Napier, 1st Baronet, of Luton Hoo in Bedfordshire (1560–1637), and a sister of the second wife of General Sir Thomas Myddelton of Chirk, his fellow Parliamentarian commander during the Civil War, a connection to the parliamentary party in the heavily royalist county of Shropshire. By Margaret he had children including:
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