A series of Ta2O5-based hybrid catalysts functionalized by both alkyl-bridged organosilica fragments and the Keggin-type heteropoly acid, Ta2O5/Si(R)Si-H3PW12O40 (R = –CH2CH2- or –C6H4–), were prepared via a one-pot co-condensation method in the presence of a triblock copolymer surfactant (P123). The materials were well characterized by spectroscopy methods, X-ray diffraction analysis, transmission electron microscopy, and nitrogen physisorption measurement to confirm the structural integrity of the Keggin unit and alkyl-bridged organosilica units in the hybrid materials, to investigate the interaction between the Ta2O5 matrix and the organic or inorganic functionalities, and to test the mesostructure, morphology, and porosity of the materials. The materials were subsequently utilized as environmentally-friendly solid acid catalysts in the transesterification of soybean oil (containing 20 wt% myristic acid) with methanol to produce fatty acid methyl esters under atmosphere refluxing. Compared with bulk H3PW12O40 and alkyl-free H3PW12O40/Ta2O5, as-prepared Ta2O5/Si(R)Si-H3PW12O40 hybrid materials with suitable concentrations of bridging alkyl groups exhibited higher reactivity toward the target reaction. This enhanced acid-catalytic reactivity after the introduction of both acidic and hydrophobic functionalities within the Ta2O5 matrix is discussed. Finally, the reusability of the hybrid materials was evaluated through three catalytic runs.