In 1882, by the age of 18, Russell was working as a cattle hand. During the harsh winter of 1886-87, when Russell was working on the O-H Ranch Judith Basin of Central Montana, he was inspired to paint. When the ranch foreman received a letter from the owner, asking how the cattle herd had weathered the winter, the foreman replied with a postcard-sized watercolor Russell had painted of gaunt steer being watched by wolves under a gray winter sky.

The ranch owner showed the postcard to friends and eventually displayed it in a shop window in Helena, Montana, after which, work began to come steadily to Russell. In 1888, he spent the summer with the Blood Indians in Alberta, Canada, an experience that can be seen in the many detailed works he created of Plains Indians.

In 1896, Russell married Nancy Cooper and the following year, they moved to Great Falls, Montana. There, working in a log cabin studio next to their home, Russell pursued painting and sculpting full-time. The studio was filled with Indian clothing, tools, weapons, cowboy gear, and other western "props" useful in accurately depicting the scenes of the Old West. It was here that his major paintings would be made. Within no time, Russell became a local celebrity and eventually gained the acclaim of critics worldwide. To this, his wife Nancy is generally given credit, as Russell kept mostly to himself. While he was working in his studio, she set up many of his shows throughout the United States and in London.

In 1916, Charles and Nancy adopted a son they named Jack. A doted father, he was often seen carrying him about town and showing him off.

Russell died on October 24, 1926 at his home in Great Falls, Montana. During his lifetime, he completed approximately 4,000 works of art. During his lifetime, Russell was also known as a colorful storyteller, and a collection of short stories called Trails Plowed Under.