Liquid coconut shell smoke (LC-SS) is used in natural food preservation for a long history. The purpose of this study was to analyze the role of LC-SS in macrophage responses during diabetic oral ulcer healing as medication. Oral ulcers were induced in the labial lower mucosa of the research subjects using a round steel blade following diabetic induction by means of alloxan. Twenty-four diabetic Wistar rats presenting oral ulcers were divided into two groups, a test group, which was given topical treatment of LC-SS and a control group, which was given benzydamine hydrochloride (BHCl). The role of LC-SS in macrophages was assessed by means of immunohistochemistry for nuclear factor kappa B (NF-κB) and tumor necrosis factor-α (TNF-α) expression. LC-SS increased macrophages compared with BHCl ( = 0.000). The LC-SS affected only TNF-α expression by stimulating NF-κB expression ( = 0.046) but did not macrophage numbers ( = 0.861). LC-SS has a stronger effect compared with BHCl on diabetic oral ulcer healing by increasing macrophage response to produce TNF-α while decreasing NF-κB expression.