The isolated unilateral aplasia of the submandibular gland (SMG) is an extremely rare condition, because most cases of congenital absence of the major salivary glands are associated with other anomalies and several major salivary glands. Worldwide, only 15 cases of isolated unilateral SMG aplasia have been reported. Here, we report a case of a 35-year-old woman with isolated unilateral SMG absence. The ipsilateral parotid gland was hypertrophied at the time of initial diagnosis, but this gland showed significant atrophy during the subsequent 3-year follow-up. This phenomenon may be associated with ipsilateral SMG aplasia, and we report this unique case along with a literature review in this paper.