Mather was associated with Edward Weston. They were close companions who collaborated on many photographs. His fame continues to overshadow Mather's considerable work from the period of their collaboration and afterwards. Mather and Weston met in 1913 and worked together until he departed for Mexico in 1923. The photographs Mather made, both alone and in collaboration with Weston, helped set the stage for the shift from pictorialism (softly focused images giving the photograph a romantic quality) to modernity. Many of her photographs were more experimental than those being produced by her contemporaries.
Mather found a dear friend and model in a young man named William Justema, who would later write about her in his memoir. Her last exhibition was held in 1931 at the M.H. de Young Memorial Museum in San Francisco. This exhibition consisted of a group of images in which objects such as seashells, chains, glass eyes, and combs were arranged in repetitive patterns to demonstrate how photography could be used to create prototypes for fabric designs. Mather's work is featured in the book, Margrethe Mather & Edward Weston: A Passionate Collaboration (W.W. Norton & Santa Barbara Museum of Art, 2001).