In 1631 Hamilton took over a force of 6,000 men to assist Gustavus Adolphus in the Thirty Years' War in Germany. He guarded the fortresses on the Oder while Gustavus fought Tilly at the Battle of Breitenfeld, and afterwards occupied Magdeburg, but his army was destroyed by disease and starvation, and after the complete failure of the expedition Hamilton returned to England in September 1634.
He now became Charles I's chief adviser in Scottish affairs. In May 1638, after the outbreak of the revolt against the new Prayer-Book, he was appointed commissioner for Scotland to appease the discontents. He described the Scots as being "possessed by the devil", and instead of doing his utmost to support the king's interests was easily intimidated by the covenanting leaders and persuaded of the impossibility of resisting their demands, finally returning to Charles to urge him to give way. It is said that he so far forgot his trust as to encourage the Scottish leaders in their resistance in order to gain their favour.
On 27 July 1638 Charles sent Hamilton back to Scotland with new proposals for the election of an assembly and a parliament, episcopacy being safeguarded but bishops being made responsible to future assemblies. After a wrangle concerning the mode of election he again returned to Charles. Having been sent back to Edinburgh on 17 September 1638, he brought with him a revocation of the prayer-book and canons and another covenant to be substituted for the national covenant. On 21 November 1638 Hamilton presided over the first meeting of the assembly in Glasgow cathedral, but dissolved it on 28 November 1638 on its declaring the bishops responsible to its authority. The assembly, however, continued to sit notwithstanding, and Hamilton returned to England to give an account of his failure, leaving the enemy triumphant and in possession.
War was now decided upon, and Hamilton was chosen to command an expedition to the Forth to menace the rear of the Scots. On arrival on 1 May 1639 he found the plan impossible, despaired of success, and was recalled in June. On 8 July 1639, after a hostile reception at Edinburgh, he resigned his commissionership. He supported Thomas Wentworth, Earl of Strafford's proposal to call the Short Parliament, but otherwise opposed him as strongly as he could, as the, chief adversary of the Scots; and he aided Henry Vane the Elder, it was believed, in accomplishing Strafford's destruction by sending for him to the Long Parliament.
Hamilton now supported the parliamentary party, desired an alliance with his nation, and persuaded Charles in February 1641 to admit some of their leaders into the council. On the death of Strafford (12 May 1641) Hamilton was confronted by a new antagonist in James Graham, 5th Earl of Montrose, who detested both his character and policy and repudiated his supremacy in Scotland.
On 10 August 1641 Hamilton accompanied Charles on his last visit to Scotland. His aim now was to effect an alliance between the king and Archibald Campbell, 8th Earl of Argyll, the former accepting Presbyterianism and receiving the help of the Scots against the English parliament, and when this failed he abandoned Charles and adhered to Argyll. In consequence he received a challenge from Lord Ker, of which he gave the king information, and obtained from Ker an apology. Montrose wrote to Charles declaring he could prove Hamilton to be a traitor. The king himself spoke of him as being "very active in his own preservation".
Shortly afterwards the plot - known as the "Incident" - to seize Argyll, Hamilton and the latter's brother, William Hamilton, Earl of Lanark, was discovered, and on 12 October 1641 they fled from Edinburgh. Hamilton returned not long afterwards, and notwithstanding all that had occurred still retained Charles's favour and confidence. He returned with him to London and accompanied him on 5 January 1642 when he went to the city after the failure to secure the five members.
In July 1642 Hamilton went to Scotland on a hopeless mission to prevent the intervention of the Scots in the impending English Civil War, and a breach then took place between him and Argyll.
Earlier, in February 1643 proposals of mediation between Charles and the parliament came from Scotland, Hamilton instigated the "cross petition" which demanded from Charles the surrender of the annuities of tithes in order to embarrass John Campbell, 1st Earl of Loudoun, the chief promoter of the project, to whom they had already been granted. This failing, he promoted a scheme for overwhelming the influence and votes of Argyll and his party by sending to Scotland all the Scottish peers then with the king, thereby preventing any assistance to the parliament coming from that quarter, while Charles was to guarantee the establishment of Presbyterianism in Scotland only. This foolish intrigue was strongly opposed by Montrose, who was eager to strike a sudden blow and anticipate and annihilate the plans of the Covenanters. Hamilton, however, gained over the queen Henrietta Maria for his project, while Montrose was condemned to inaction. Hamilton's scheme, however, completely failed. He had no control over the parliament. He was unable to hinder the meeting of the convention of the estates which assembled without the king's authority, and his supporters found themselves in a minority.
Finally, on refusing to take the Covenant, Hamilton and Lanark were obliged to leave Scotland. They arrived at Oxford on 16 December 1643. Hamilton's conduct had at last incurred Charles's resentment and he was sent, in January 1644, a prisoner to Pendennis Castle, in 1645 being removed to St Michael's Mount, where he was liberated by Lord Fairfax's troops on 23 April 1646.
In 1646 Charles conferred on the Duke the heritable office of Keeper of Holyroodhouse.
Subsequently he showed great activity in the futile negotiations between the Scots and Charles at Newcastle. In 1648, in consequence of the seizure of Charles by the army in 1647, Hamilton obtained a temporary influence and authority in the Scottish parliament over Argyll, and led a large force into England in support of the king on 8 July 1648. He showed complete incapacity in military command; was kept in check for some time by Lambert; and though outnumbering the enemy by 24,000 to about 9000 men, allowed his troops to disperse over the country and to be defeated in detail by Cromwell during the three days 17 - 19 August 1648 at the so-called Battle of Preston, being himself taken prisoner on 25 August.
Hamilton, during his unfortunate career, had often been suspected of betraying the king's cause, and, as an heir to the Scottish throne, of intentionally laying into the hands of the Covenanters with a view of procuring the crown for himself.
The charge was brought against him as early as 1631 when he was levying men in Scotland for the German expedition, but Charles gave no credence to it and showed his trust in Hamilton by causing him to share his own room. The charge, however, always clung to him, and his intriguing character and hopeless management of the king's affairs in Scotland gave colour to the accusation. There seems, however, to be no real foundation for it. His career is sufficiently explained by his thoroughly weak and egotistical character. He took no interest whatever in the great questions at issue, was neither loyal nor patriotic, and only desired peace and compromise to avoid personal losses. "He was devoid of intellectual or moral strength, and was therefore easily brought to fancy all future tasks easy and all present obstacles insuperable". A worse choice than Hamilton could not possibly have been made in such a crisis, and his want of principle, of firmness and resolution, brought irretrievable ruin upon the royal cause.
Following the death of his three sons, the dukedom passed by special remainder to his brother William Hamilton, Earl of Lanark. On the latter's death at Worcester in 1651 the Scottish titles reverted to the 1st duke's eldest daughter, Anne. She married William Douglas, Earl of Selkirk, who was created Duke of Hamilton for life.