The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.