Ketonization of fatty acids into fatty ketones is a potential route for producing high-value chemicals including bioderived lube base oil. In the present work, the catalytic selectivity and deactivation during the ketonization of C-18 fatty acids having different unsaturation degrees over a TiO2 catalyst were rigorously investigated. The results demonstrated that the yield of fatty ketone gradually decreased with increasing unsaturation degree, while byproducts such as methyl ketones and olefins were produced owing to McLafferty rearrangement. It was verified that carboxylic acids longer than C-5 can be decomposed via this pathway, the rate of which increased with the carbon chain length. In the ketonization of unsaturated fatty acids, the McLafferty rearrangement and cracking produced conjugated polyunsaturated olefins (e.g., dienes), which could be readily decomposed to coke. The results implied that the ketonization of natural fatty acids requires the presaturation of C=C bonds for increasing the fatty ketone yield and inhibiting catalyst deactivation. Indeed, the ketonization of a natural fatty acid mixture obtained by palm oil hydrolysis exhibited diminished fatty ketone selectivity and rapid catalyst deactivation, owing to the presence of unsaturated fatty acids. In contrast, the ketonization of a saturated fatty acid mixture obtained by hydrogenative hydrolysis exhibited a high fatty ketone yield (similar to 90%) and negligible deactivation.