We developed a chemical sensor based on a hetero-core optical fiber structure where lipid films coat a cylindrical cladding. Two lipids were applied to the fiber surface: oleic acid and phosphoric acid di(2-ethylhexyl) ester. Experiments were performed to observe the differential optical loss spectra over the measured spectral region in response to each chemical substance. The oleic acid- and PAEE-coated sensors induced optical losses of approximately 0.4 and 0.2 dB, respectively, for a refractive index difference of 0.0008 between water and quinine. Compared with a conventional hetero-core optical fiber sensor based on surface plasmon resonance, which uses double-layer films of gold and lipid, the proposed sensors scheme showed the different sensitivity to chemical substances and could detect a wide range of chemical substances such as quinine. The response of the proposed sensor was reproducible at concentrations of >0.01 mM. Changing the type of lipid in the film controls the selectivity of chemical substances. The proposed sensor works based on hydrocarbon groups of fatty acids or carboxyl groups that form self-assembled monolayers on the fiber. The exposure of carboxyl groups at the surface of the fatty acids may be involved in the sensor response.