Andrew was the youngest of the five children of Illustrator and Artist N.C. (Newell Convers) Wyeth and his wife, Carolyn Bockius Wyeth. He was born July 12, 1917, on Henry David Thoreau's 100th birthday. Due to N.C.'s fond appreciation of Henry David Thoreau, he found this both coincidental and exciting. N.C. was an attentive father, fostering each of the children's interests and talents. The family was close, spending time reading together, taking walks, fostering "a closeness with nature" and developing a feeling for Wyeth family history.

In the 1920s, Wyeth's father had become a Celebrity, and the family often had celebrities as guests, such as F. Scott Fitzgerald and Mary Pickford. The home bustled with creative activity and competition. N.C. and Carolyn's five children were all talented. Henriette Wyeth Hurd, the eldest, became a well-known Painter of portraits and still lifes. Carolyn, the second child, was also a Painter. Nathaniel Wyeth, the third child, was a successful Inventor. Ann was a musician at a young age and became a Composer as an adult. Andrew was the youngest child.

In the early 1930s, Wyeth began painting Anna and Karl Kuerner, his neighbors in Chadds Ford. Like the Olsons, the Kuerners and their farm were one of Wyeth's most important subjects for nearly 50 years. As a teenager, Wyeth would walk the hills of the Kuerner Farm. Soon, he became close friends with Karl and Anna. Eventually, they invited Wyeth into their house. Inside, Wyeth documented the Kuerners, their home, and their life.

Wyeth created nearly 300 drawings, watercolors and tempera paintings at Olson's from 1937 to the late 1960s. Because of Wyeth's popularity, the property was designated a National Historic Landmark in June 2011.

In 1940, Wyeth married Betsy James, whom he met in 1939 in Maine. Christina Olson, who would become the model for the iconic 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. 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).

N.C. also fostered an inner self-confidence to follow one's own talents without thought of how the work is received. N.C. wrote in a letter to Wyeth in 1944:

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.

Andrew was home-tutored because of his frail health. Like his father, the young Wyeth read and appreciated the poetry of Robert Frost and the writings of Henry David Thoreau and studied their relationships with nature. Music and movies also heightened his artistic sensitivity. One major influence, discussed at length by Wyeth himself, was King Vidor's The Big Parade. He claimed to have seen the film, which depicted family dynamics similar to his own, "a hundred-and-eighty-times" and believed it had the greatest influence on his work. Vidor later made a documentary, Metaphor, where he and Wyeth discuss the influence of the film on his paintings, including Winter 1946, Snow Flurries, Portrait of Ralph Kline and Afternoon FLIGHT of a Boy up a Tree.

It was at the Olson farm in Cushing, Maine, that he painted Christina's World (1948). Perhaps his most famous image, it depicts his neighbor, Christina Olson, sprawled on a dry field facing her house in the distance. Wyeth was inspired by Christina, who, crippled from (undiagnosed) polio and unable to walk, spent most of her time at home.

Admirers of Wyeth's art believe that his paintings, in addition to their pictorial formal beauty, contain strong emotional currents, symbolic content, and underlying abstraction. Most observers of his art agree that he is skilled at handling the medium of egg tempera (which uses egg yolk as its medium) and watercolor. Wyeth avoided using traditional oil paints. His use of light and Shadow lets the subjects Illuminate the canvas. His paintings and titles suggest sound, as is implied in many paintings, including Distant Thunder (1961) and Spring Fed (1967). Christina's World became an iconic image, a status unmet to even the best paintings, "that registers as an emotional and cultural reference point in the minds of millions."

Wyeth was a visual Artist, primarily Classified as a realist Painter, like Winslow Homer or 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 developed a considerable fortune as a result. Yet there have been conflicting views by critics, curators and historians 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, 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.

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.

With his father’s guidance, he mastered figure study and watercolor, and later learned egg tempera from his brother-in-law Peter Hurd. He studied art history on his own, admiring many masters of Renaissance and American painting, especially Winslow Homer.