Abstract: SLC13A5 (solute carrier family 13 member 5) is an important transporter that mediates the transmembrane uptake of extracellular citrate. By regulating cytosolic citrate and acetyl-CoA levels, SLC13A5 participates in energy metabolism, lipid synthesis, inflammatory responses, and the maintenance of neuronal homeostasis. This review focuses on the SLC13A5-driven metabolic–inflammatory axis and systematically summarizes its roles and underlying mechanisms in various diseases, as well as recent advances in targeted interventions. SLC13A5-mediated citrate metabolic reprogramming affects lipid synthesis, oxidative stress, and inflammatory signaling, thereby establishing a regulatory network that links metabolic dysfunction with inflammatory responses. In metabolic diseases, upregulated SLC13A5 promotes hepatic de novo lipogenesis, exacerbates insulin resistance, and drives the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) toward inflammatory and fibrotic stages. In inflammation-related diseases, increased SLC13A5 expression enhances citrate metabolic flux, promotes the production of inflammatory mediators, and amplifies inflammatory responses. In cancer, SLC13A5 contributes to metabolic reprogramming and the maintenance of an inflammatory tumor microenvironment, thereby supporting tumor cell growth and proliferation. In the nervous system, loss of SLC13A5 function or abnormal SLC13A5 expression disrupts neuronal energy metabolism, neurotransmitter homeostasis, and neural network function, leading to epilepsy and neurodevelopmental disorders. This review further summarizes SLC13A5-targeted strategies, including small-molecule inhibitors, antisense oligonucleotides, and gene replacement therapy, and discusses the translational challenges such as tissue selectivity, central nervous system safety risks, species differences, and limited delivery efficiency. This review provides a theoretical basis for investigating the mechanisms of SLC13A5-related diseases and developing precision therapeutic strategies.