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In 1831, Dix established a school for girls in Boston, operating it until 1836, when she had health issues in the nature of nervous exhaustion. Her physician recommended that she travel to Europe to help her health. It was there that she met other reformers who inspired her to take up the cause of rights for the mentally ill, including Elizabeth Fry, Samuel Tuke and William Rathbone. In 1836 she traveled to England, where she met the Rathbone family and lived with them at their ancestral mansion in Liverpool. The Rathbones were Quakers and prominent social reformers.
After returning to America, in 1840-41 Dix conducted a statewide investigation of care for the mentally ill poor in Massachusetts. At the time, those who were mentally ill people and who could not care for themselves and lacked family support were looked after by individuals hired by local government. This system was unregulated and resulted in widespread abuse. Dix published a scathing report about this system to the state legislature, in which she wrote: "I proceed, Gentlemen, briefly to call your attention to the present state of Insane Persons confined within this Commonwealth, in cages, stalls, pens! Chained, naked, beaten with rods, and lashed into obedience." Her lobbying resulted in a bill to expand the state's mental hospital in Worcester.
In 1844 Dix undertook a review of all the counties, jails and almshouses in New Jersey and prepared a report for the New Jersey Legislature similar to the one she had done in Massachusetts. She urged the legislature to appropriate funds to construct a facility for the care and treatment of the mentally ill. One of the people she worked with was a man who had once been a respected legislator and jurist, who suffered from a mental illness in his old age. Dix found him lying on a small bed in a basement room of the county almshouse, in a state of poor care. She wrote: "This feeble and depressed old man, a pauper, helpless, lonely, and yet conscious of surrounding circumstances, and not now wholly oblivious of the past — this feeble old man, who was he?" Many members of the legislature knew the man she was writing about. She met with legislators and held group meetings. Her efforts resulted in a bill passed for the establishment of a state facility.
Dix traveled from New Hampshire to Louisiana, documenting the condition of the poor mentally ill, making reports to state legislatures, and working with committees to draft the enabling legislation and appropriations bills needed. In 1846, Dix traveled to Illinois to study mental illness. While there, she fell ill and spent the winter in Springfield. She submitted a report to the January 1847 legislative session, which adopted legislation to establish Illinois' first state mental hospital. In 1848, Dix visited North Carolina, where she again called for reform in the care of mentally ill patients. Her first attempt to bring reform to North Carolina was denied. However, after gaining the support of a board member's wife, the bill for reform was approved. In 1849, when the (North Carolina) State Medical Society was formed, the legislature authorized construction of an institution in Raleigh for the care of mentally ill patients. The Goldsboro Hospital for the Negro Insane was also built in the Piedmont area of the segregated state. She was also instrumental in the founding of the first public mental hospital in Pennsylvania, the Harrisburg State Hospital.
Dix turned her sights on a federally funded program. In August of 1850, Dix wrote to President Millard Fillmore, urging support for her proposal in Congress for land grants to finance asylums for the impoverished mentally ill. It was not an issue that enjoyed wide support, but Fillmore saw the issue through a compassionate lens rather than a political one. He and Dix became friends, meeting in person and corresponding, continuing well after Fillmore's presidency.
The culmination of her work led to a Bill for the Benefit of the Indigent Insane. Under this legislation it was proposed that the federal government would set aside 12,225,000 acres of Federal land, with 10,000,000 acres to be used for the benefit of the mentally ill and the remainder for the "blind, deaf, and dumb". Proceeds from its sale would be distributed to the states to build and maintain asylums. Dix's land bill passed both houses of the United States Congress, and it looked like she had achieved something remarkable.
Unfortunately for Dix, when the bill passed, her friend Millard Fillmore was no longer the President. In 1854, President Franklin Pierce vetoed the bill. He took the position that social welfare was the responsibility of the states. In his veto message, Pierce said that the federal government should not commit itself to social welfare, which was properly the responsibility of the states.
Dix was devastated by the defeat of her land bill. In 1855 she traveled to England and Europe, where she reconnected with the Rathbones and conducted investigations of Scotland's madhouses that resulted in the formation of the Scottish Lunacy Commission. Dix visited the asylums of Rome, where she sought an audience with Pope Pius IX. The Pontiff was receptive to Dix's ideas and visited the asylums himself where he was shocked at the conditions he observed. He thanked Dix for her work, saying in a second audience with her that "a woman and a Protestant, had crossed the seas to call his attention to these cruelly ill-treated members of his flock."
Dix later returned to the United States and during the Civil War she served as Superintendent of Army Nurses for the Union Army, where she was praised for her even-handed treatment of both Union and Confederate patients. These included 5,000 wounded Confederate soldiers left behind when Robert E. Lee's army retreated from Gettysburg. She remained an active advocate for the welfare of both the mentally ill and of prisoners until poor health rendered her incapable of continuing on in her crusade. She died on July 17, 1887.
When the private papers of Millard Fillmore were discovered after his death, they included over 150 letters that passed between Fillmore and Dorothea Dix. The correspondence spanned nearly twenty years, exposing the friendship of these two prominent Americans, a friendship was known to few during their lifetimes. It has been published in a book entitled The Lady and The President.
The bill that Pierce vetoed is considered by some historians as a landmark in social welfare legislation in the United States. Pierce's veto established a precedent for federal non-participation in social welfare that lasted over 70 years, until the New Deal of the 1930s. No further federal legislation on mental health occurred for over 90 years until July 3, 1946 when the National Mental Health Act was signed into law by President Harry Truman, establishing federal mental health policy. It was unfortunate that Millard Fillmore's civility and compassion on this issue was not passed on to his successor. Pierce's coldness on this issue permitted injustice to continue for almost a century, something that Fillmore would certainly have not allowed.