Smith was active as an artist in Lynchburg, Virginia in the late 19th and early 20th-centuries. In 1895, she and Bernhard Gutmann founded the Lynchburg Art League. In the 1890s Smith studied art in Paris for two years and, during that same decade, became chair of Randolph-Macon Woman's College's art department. A cousin of the institution's first president, William Waugh Smith, she held that
It was at Louise's suggestion that renowned artist, William Merritt Chase painted the formal portrait of William Waugh Smith, presented to the school in 1907 by the senior class of that year.
The first art professor on the college's faculty, it was under her direction that the college held its First Annual Exhibition in 1911, believed to be the first exhibition of modern art held on a college campus anywhere in the United States. It was from this series of exhibitions—which continue to this day—that the idea of a permanent art collection grew, and the first acquisition was made in 1914 from the 4th Annual Exhibition.
During her academic career Smith also taught French at the College, and invited prominent artists of her acquaintance to come and speak to the student body. One of Smith's pupils included Georgia Weston Morgan, who also became a prominent figure in Lynchburg's artistic scene.
At her death she was buried in the Warrenton Cemetery in Warrenton, Virginia. Professor Smith ensured the continued growth of the College's collection with a 1928 bequest to establish an acquisition fund.