The series begins with the arrival of Dr. Andrew "Andy" Brown (Treat Williams), a widower who leaves his successful job as a top Manhattan neurosurgeon to live in a small Colorado town, bringing his nine-year-old daughter Delia (Vivien Cardone) and 15-year-old son Ephram (Gregory Smith) with him. He chooses the town of Everwood because his late wife had told him of her emotional attachment to the town. Many of the story lines revolve around settling into a new town, dealing with the death of the mother and wife of the family, and the growing relationship between Andy and his son, who did not interact much in New York, due to the demands of Andy's job. Andy at first finds some conflict with Dr. Harold Abbott (Tom Amandes), with whom his professional opinions differ. However, Harold's cranky demeanor and Andy's passive, cheerful attitude prove to mesh well, and the two begin a friendly rivalry. Ephram continually struggles with his emerging adolescence, his studies as a classical pianist, and his crush on Amy (Emily VanCamp), Harold's daughter.

The beginning of Season 2 reveals Colin's fate. The entire town blames Andy for "killing" Colin. They stop going to his practice and shun his children. Andy stands by his decision and eventually admits to Ephram that he could have saved Colin's life, but he would have been mentally and physically disabled and, at Colin's insistence, promised that he would not let him live that way.

The third season opens with Andy receiving a letter from Madison telling him that she is in Denver, and is not going to tell him her decision regarding the pregnancy and she wants no further contact. Andy contemplates telling Ephram, but Harold convinces him not to do so, for the sake of Ephram and Amy.

The fourth season opens with Edna and her husband Irv planning a vow-renewal ceremony. Rose is recovering well, and Jake has moved in with Nina. Amy lives at home while attending Colorado A&M, instead of Princeton, to help Rose during her convalescence. Bright starts his second year at Everwood Community College and has moved into an apartment. A medical student, Reid, has caught Amy's eye, and Amy convinces Bright to let Reid be his roommate. At the request of Delia, who desperately misses him, Ephram returns from Europe in time to attend the end of Irv and Edna's ceremony.