Millais' "Christ In The House Of His Parents" (1850) was highly controversial because of its realistic portrayal of a working class Holy Family labouring in a messy carpentry workshop. Later works were also controversial, though less so. Millais achieved popular success with "A Huguenot" (1852), which depicts a young couple about to be separated because of religious conflicts. He repeated this theme in many later works. All these early works were painted with great attention to detail, often concentrating on the beauty and complexity of the natural world. In paintings such as "Ophelia" (1852) Millais created dense and elaborate pictorial surfaces based on the integration of naturalistic elements. This approach has been described as a kind of "pictorial eco-system".
This style was promoted by the critic John Ruskin, who had defended the Pre-Raphaelites against their critics. Millais' friendship with Ruskin introduced him to Ruskin's wife Effie. Soon after they met she modeled for his painting "The Order of Release". As Millais painted Effie they fell in love. In 1855, after her marriage to Ruskin was annulled, Effie and John Millais married. He and Effie eventually had eight children. Their youngest son, John Guille Millais, became a notable naturalist and wildlife artist.
After his marriage, Millais began to paint in a broader style, which was condemned by Ruskin as "a catastrophe". It has been argued that this change of style resulted from Millais' need to increase his output to support his growing family. Unsympathetic critics such as William Morris accused him of "selling out" to achieve popularity and wealth. His admirers, in contrast, pointed to the artist's connections with Whistler and Albert Moore, and influence on John Singer Sargent. Millais himself argued that as he grew more confident as an artist, he could paint with greater boldness. In his article "Thoughts on our art of Today" (1888) he recommended Velázquez and Rembrandt as models for artists to follow. Paintings such as "The Eve of St. Agnes" and "The Somnambulist" clearly show an ongoing dialogue between the artist and Whistler, whose work Millais strongly supported. Other paintings of the late 1850s and 1860s can be interpreted as anticipating aspects of the Aesthetic Movement. Many deploy broad blocks of harmoniously arranged color and are symbolic rather than narratival.
Later works, from the 1870s onwards demonstrate Millais' reverence for old masters such as Joshua Reynolds and Velázquez. Many of these paintings were of an historical theme and were further examples of Millais' talent. Notable among these are "The Two Princes Edward and Richard in the Tower" (1878), "The Northwest Passage" (1874) and the "Boyhood of Raleigh" (1871). Such paintings indicate Millais' interest in subjects connected to Britain's history and expanding empire. Millais also achieved great popularity with his paintings of children, notably "Bubbles" (1886) – famous, or perhaps notorious, for being used in the advertising of Pears soap – and "Cherry Ripe". His last project (1896) was to be a painting entitled "The Last Trek". Based on his illustration for his son's book, it depicted a white hunter lying dead in the African veldt, his body contemplated by two Africans.
This fascination with wild and bleak locations is also evident in his many landscape paintings of this period, which usually depict difficult or dangerous terrain. The first of these, "Chill October" (1870) was painted in Perth, near his wife's family home. It was the first of the large-scale Scottish Landscapes Millais painted periodically throughout his later career. Usually autumnal and often bleakly unpicturesque, they evoke a mood of melancholy and sense of transience that recalls his cycle-of-nature paintings of the later 1850s, especially "Autumn Leaves" and "The Vale Of Rest", though with little or no direct symbolism or human activity to point to their meaning.
Millais was also very successful as a book illustrator, notably for the works of Anthony Trollope and the poems of Tennyson. His complex illustrations of the parables of Jesus were published in 1864. His father-in-law commissioned stained-glass windows based on them for Kinnoull parish church, Perth. He also provided illustrations for magazines such as Good Words. In 1869 he was recruited as an artist for the newly founded weekly newspaper The Graphic.
Millais was elected as an associate member of the Royal Academy of Arts in 1853, and was soon elected as a full member of the Academy, in which he was a prominent and active participant. He was granted a baronetcy in 1885. After the death of The Lord Leighton in 1896, Millais was elected President of the Royal Academy, but he died later in the same year from throat cancer. He was buried in St Paul's Cathedral.