In 1937, at age twenty, Wyeth had his first one-man exhibition of watercolors at the Macbeth Gallery in New York City. The entire inventory of paintings sold out, and his life path seemed certain. His style was different from his father’s: more spare, “drier,” and more limited in color range. He stated his belief that “the great danger of the Pyle school is picture-making.” He did some book illustrations in his early career, but not to the extent that N.C. Wyeth did.

On May 15, 1940, Wyeth married Betsy James, whom he met in 1939 in Maine. Christina Olson, who was to become the model for Christina’s World, met Wyeth through an introduction by Betsy. His wife, Betsy, had an influence on Andrew as strong as that of his father, such that N.C. Wyeth began to resent her. She played an important role managing his career. She was once quoted as saying, “I am a director and I had the greatest actor in the world.” Their first child, Nicholas, was born in 1943, followed by James (“Jamie”) three years later. Wyeth painted portraits of both children (Nicholas of his older son and Faraway of his younger son).

In October 1945, his father and his three-year-old nephew, Newell Convers Wyeth II (b. 1941), were killed when their car stalled on railroad tracks near their home and was struck by a train. Wyeth referred to his father’s death as a formative emotional event in his artistic career, in addition to being a personal tragedy. Shortly afterwards, Wyeth’s art consolidated into his mature and enduring style.

Wyeth was a visual artist, primarily classified as a realist painter, like Winslow Homer or Thomas Eakins. In a Life magazine article in 1965, Wyeth said that although he was thought of as a realist, he thought of himself as an abstractionist: “My people, my objects breathe in a different way: there’s another core—an excitement that’s definitely abstract. My God, when you really begin to peer into something, a simple object, and realize the profound meaning of that thing—if you have an emotion about it, there’s no end.”

Wyeth’s art has long been controversial. He developed technically beautiful works, had a large following and accrued a considerable fortune as a result. Yet critics, curators and historians have offered conflicting views about the importance of his work. Art historian Robert Rosenblum was asked in 1977 to identify the “most overrated and underrated” artists of the 20th century. He provided one name for both categories: Andrew Wyeth.

In 1986, extensive coverage was given to the revelation of a series of 247 studies of the German-born Helga Testorf, whom Wyeth met while she was attending to Karl Kuerner at his farm. Wyeth painted her over the period 1971–85 without the knowledge of either his wife or Helga’s husband, John Testorf. Helga, a caregiver with nursing experience, had never modeled before but quickly became comfortable with the long periods of posing, during which he observed and painted her in intimate detail. The Helga pictures are not an obvious psychological study of the subject, but more an extensive study of her physical landscape set within Wyeth’s customary landscapes. She is nearly always portrayed as unsmiling and passive; yet, within those deliberate limitations, Wyeth manages to convey subtle qualities of character and mood, as he does in many of his best portraits. This extensive study of one subject in differing contexts and emotional states is unique in American art.

In 1986, Philadelphia publisher and millionaire Leonard E.B. Andrews (1925–2009) purchased almost the entire collection, preserving it intact. Wyeth had already given a few Helga paintings to friends, including the famous Lovers, which had been given as a gift to Wyeth’s wife. The works were exhibited at the National Gallery of Art in 1987 and in a nationwide tour. There was extensive criticism of both the 1987 exhibition and the subsequent tour. The show was “lambasted” as an “absurd error” by John Russell and an “essentially tasteless endeavor” by Jack Flam, coming to be viewed by some people as “a traumatic event for the museum.” The curator, Neil Harris, labeled the show “the most polarizing National Gallery exhibition of the late 1980s,” himself admitting concern over “the voyeuristic aura of the Helga exhibition.”

In a 2007 interview, when Wyeth was asked if Helga was going to be present at his 90th birthday party, he said “Yeah, certainly. Oh, absolutely,” and went on to say, “She’s part of the family now. I know it shocks everyone. That’s what I love about it. It really shocks ’em.”

On January 16, 2009, Andrew Wyeth died in his sleep in Chadds Ford, Pennsylvania, after a brief illness. He was 91 years old.

Because of Wyeth’s profile, the property was designated a National Historic Landmark in June 2011.

The Kuerner Farm is available to tour through the Brandywine River Museum, as is the nearby N. C. Wyeth House and Studio; in 2011, the farm was declared a National Historic Landmark, based on its association with Wyeth.

His son Jamie Wyeth followed his father’s and grandfather’s footsteps, becoming the third generation of Wyeth artists. Andrew would be the role model and teacher to his son Jamie that his father, N.C., had been to him. The artistic history is told in James H. Duff’s An American Vision: Three Generations of Wyeth Art. Betsy Wyeth died in April 2020, aged 98.