In 1826, as a young man, Trevelyan joined the East India Company as a Writer and was posted to the Bengal Civil Service at Delhi, India. There, by a combination of diligence and self-discipline together with his outstanding intellectual talents he achieved rapid promotion. He occupied several important and influential positions in various parts of India, but his priggish and often indiscreet behaviour endeared him to few of his colleagues and involved him in almost continual controversy.

He entered the East India Company's Bengal civil Service as a Writer in 1826, having displayed from an early age a great proficiency in Asian languages and dialects. On 4 January 1827, Trevelyan was appointed assistant to Sir Charles Theophilus Metcalfe, the commissioner at Delhi, where, during a residence of four years, he was entrusted with the conduct of several important missions. For some time he acted as guardian to the youthful Madhu Singh, the Rajah of Bhurtpore. He also worked to improve the condition of the native population. He abolished the transit duties by which the internal trade of India had long been fettered. For these and other services, he received the special thanks of the governor-general in council. Before leaving Delhi, he donated personal funds for construction of a broad street through a new suburb, then in course of erection, which thenceforth became known as Trevelyanpur.

In 1831, he moved to Calcutta, and became deputy secretary to the government in the political department. Trevelyan was especially zealous in the cause of education, and in 1835, largely owing to his persistence, government was led to decide in favour of the promulgation of European literature and science among the Indians. An account of the efforts of government, entitled On the Education of the People of India, was published by Trevelyan in 1838. In April 1836, he was nominated secretary to the Sudder board of revenue, an office he had held until his return in January 1838.

On 23 December 1834, while in India, he married Hannah More Macaulay, sister of Lord Macaulay, who was then a member of the supreme council of India, and one of his closest friends. Their only son, who inherited the Baronetcy on his father's death, was Sir George Trevelyan, 2nd Baronet, the statesman. Hannah Macaulay Trevelyan died on 5 August 1873.

On 21 January 1840, he entered on the duties of assistant secretary to Her Majesty's Treasury in London, and discharged the functions of that office for nineteen years. In Ireland he administered the relief works of 1845–47, when upwards of 734,000 men were employed by the government during the Great Famine. Altogether, about a million people in Ireland are reliably estimated to have died of starvation and epidemic disease between 1846 and 1851, and some two million emigrated in a period of a little more than a decade (1845–55). On 27 April 1848 he was made a KCB in reward of his services.

A letter from Trevelyan to Lord Monteagle of Brandon and an article in The Times reinforced Trevelyan's belief that Ireland needed to heal itself from within, without the substantial aid from the British Government. Both were written in the second year of the blight, 1846, when over ninety percent of the potato crop had been destroyed. With this knowledge, it is easy to see how Trevelyan would have persuaded Lord Monteagle in his letter to believe that "the government establishments are strained to the utmost to alleviate this great calamity and avert this danger" as was within their power so to do. Trevelyan praised the government and denounced the Irish gentry in his letter, blaming them for the famine. He believed that it was not the government's responsibility to provide supplies of food or increase land productivity, but the landlords'. The Times agreed with Trevelyan, faulting the gentry for not instructing their proprietors to improve their estates and not planting crops other than the potato. In his letter to Lord Monteagle, Trevelyan identified the gentry with the "defective part of the national character" and chastised them for expecting the government to fix everything, "as if they have themselves no part to perform in this great crisis." By blaming the famine on the gentry, Trevelyan justified the actions—or inaction—of the British Government.

Trevelyan was appointed KCB on 27 April 1848. Three decades later on 2 March 1874, he was created the first Trevelyan baronet, of Wallington.

The potato blight eventually spread to the Western Highlands of Scotland, causing similar destitution. In 1851, in response to that crisis, Trevelyan and Sir John McNeill founded the Highland and Island Emigration Society. From 1851 until its termination in 1858, the society sponsored the emigration of around 5,000 Scots to Australia. In 1853, Trevelyan proposed the organisation of a new system of admission into the civil Service. The Northcote–Trevelyan Report, signed by himself and Sir Stafford Northcote in November 1853, entitled The Organisation of the Permanent Civil Service, laid the foundation for securing the admission of qualified and educated persons into situations which were previously much at the disposal of aristocratic and influential families.

In conjunction with his cousin, Sir Walter Calverley Trevelyan, he edited the Trevelyan Papers (Camden Society 1856, 1862, 1872).

His letters to the Times, with the signature of Indophilus, he collected with Additional Notes in 1857; 3rd edit. 1858. Several of his addresses, letters, and speeches were also published.

In 1858, Lord Harris resigned the governorship of the presidency of Madras, and Trevelyan was offered the appointment. Having maintained his knowledge of oriental affairs by close attention to all subjects affecting the interest of India, he entered upon his duties as governor of Madras in the spring of 1859. He soon became popular in the presidency, and in a great measure through his conduct in office, the natives became reconciled to the government. An assessment was carried out, a police system organised in every part, and, contrary to the traditions of the East India Company, land was sold in fee simple to any one who wished to purchase. These and other reforms introduced or developed by Trevelyan won the gratitude and esteem of the Madras population.

Trevelyan was Governor of Madras from 1859 to 1860, and Indian Finance Minister from 1862 to 1865. A reformer of the civil Service, he is widely regarded as the founder of the modern British civil Service.

All went well until February 1860. Towards the close of 1859, James Wilson was appointed financial member of the legislative council of India. At the beginning of the new year, he proposed a plan of retrenchment and taxation by which he hoped to improve the financial position of the British administration: his plan was introduced at Calcutta on 18 February, and transmitted to Madras. On 4 March, an open telegram was sent to Calcutta implying an adverse opinion of the governor and council of Madras. On 9 March, a letter was sent to Madras stating the central government's objection to the transmission of such a message in an open telegram at a time when native feeling could not be considered stable. At the same time, the representative of the Madras government in the legislative council of India was prohibited from following the instructions of his superiors to lay their views upon the table and to advocate on their behalf. On 21 March, another telegram was sent to Madras declaring the bill would be introduced and referred to a committee which was due to report in five weeks. On 26 March, opinions among Trevelyan and his council were recorded and, on his authority, the document found its way into the papers.

In 1862, Trevelyan returned to India as Finance minister. His tenure of office was marked by important administrative reforms and by extensive measures for the development of natural resources in India by means of public works. In 1862, Colonel Douglas Hamilton was given a roving commission by Trevelyan to conduct surveys and make drawings for the Government of all the hill plateaus in Southern India which were likely to suit as Sanitaria, or quarters for European troops. On his return home in 1865, he became engaged in discussions of the question of army purchase, on which he had given evidence before the royal commission in 1857. Later he was associated with a variety of social questions, such as charities, pauperism, and the like, and in the treatment of these.

Trevelyan married, secondly, on 14 October 1875, Eleanor Anne, daughter of Walter Campbell of Islay.

When his cousin Walter Calverley Trevelyan, 6th Baronet, of Nettlecombe, died at Wallington on 23 March 1879, both his marriages were childless, so he left his north-country property to Charles. A biographer from the family notes that Walter changed his will in 1852, having been impressed by Charles' son; the young George Otto Trevelyan had been one of the couple's visitors and received hints of the secret will. The modest social position of the family was suddenly elevated to one of wealth and property, recorded as an important event in the history of the baronetcy.

He retained to the last all his native Energy of temperament. He was a staunch Liberal, and gave his support to the Liberal cause in Northumberland, while residing at Wallington Hall in that county. He is drawn by Trollope in The Three Clerks, which was published in 1857 in 3 volumes, under the pseudonym Sir Gregory Hardlines. Trevelyan died at 67 Eaton Square, London, on 19 June 1886, aged 79.