The 1850s were a period of dangerous and rising tensions in the United States, but it was also a time of great intellectual progress and a flourishing of intellectual development in cities such as Boston. In a sense, therefore, it was a decade of contradictions and debate, and the great divide in values and patriotic sentiment would cause the country to erupt in civil war in 1861. This divide was between southeastern states, which were based on a cotton- and tobacco-producing plantation system, and northeastern states, whose economy was largely industrial. Although slavery had been outlawed in the North, it was legal in the South, and slave labor remained the basis of the southern economy. Much of the debate in the 1850s was about the destiny of the large middle and western sections of the country, to which settlers were moving in great numbers. Congress decided whether new states would be slaveholding, and this designation largely determined whether they would assume Southern or Northern values.

The question of slavery, therefore, was an extremely important and divisive issue of the day, hotly debated by politicians, writers, intellectuals, and ordinary people. Holmes and other figures lectured and wrote about the possible abolition of slavery in the territories, which Holmes opposed because he feared the consequences of the building conflict between the South and the North. American intellectuals also spoke and wrote about other major issues of the day, such as women's rights (women were barred from voting and experienced severe discrimination) and new, large-scale immigration. Massive numbers of immigrants, particularly from Ireland because of the Great Famine there, settled in the United States in the 1850s.

Holmes's hometown of Boston was famous in the 1850s for its vibrant intellectual culture full of social reformers and literary figures, and historians often characterize this period as a renaissance of literature and philosophy with Boston at its hub. Influential figures, including Ralph Waldo Emerson, Henry David Thoreau, Margaret Fuller, and James Russell Lowell, lived and wrote in Boston, which was a commercially successful and rapidly expanding city at this time. Emerson was the chief proponent of transcendentalism, a post-Romantic literary and philosophical movement that stressed the unity of all things and the revelation of deep truths to be found in personal experience as well as in reason. Thoreau (an influential early environmentalist) and Fuller (who helped found the American feminist movement) also were transcendentalists, and they met in conversation circles to develop their theories and inspire each other.

Also of great importance in Boston in the 1850s were the elite members of the white male Protestant ruling class, who gathered in places like Harvard College. As a prominent member of the faculty at Harvard Medical School (although he upset the Harvard elite by speaking against its Calvinist doctrine in various public addresses), Holmes was a member of this class. He was also one of Boston's leading intellectual figures, famous for his conversational skills, and he met in conversation circles that debated issues ranging from art to science. A practicing physician and medical researcher, Holmes was interested throughout his life in advancing medical science and promoting awareness in the public. He was instrumental in encouraging the widespread use of microscopes by physicians and in alerting the public to a contagious condition found in women during childbirth. Although he was not a transcendentalist and even spoke out against its doctrines, Holmes later came to appreciate Emerson's ideas and wrote an influential biography of the philosopher.