The show's first ten seasons follow Lassie's adventures in a small farming community. Fictional eleven-year-old Jeff Miller, his mother, and his grandfather are Lassie's first human companions until seven-year-old Timmy Martin and his adoptive parents take over in the fourth season. When Lassie's exploits on the farm end in the eleventh season, she finds new adventures in the wilderness with a succession of United States Forestry Service workers. After traveling without human leads for a year, Lassie finally settles at a children's home for her final two syndicated seasons.

Lassie found critical favor from its début and won two Emmy awards in its first years. Stars Jan Clayton and June Lockhart were nominated for Emmys. Merchandise produced during the show's run included books, a Halloween costume, clothing, toys, and other items. Campbell's Soup, the show's life-long sponsor, offered two premiums (a ring and a wallet), and distributed thousands to fans. A multi-part episode was edited into the feature film, Lassie's Great Adventure and released in August 1963.