A systematic study on the influence of fillers on the structural properties at micro and nanoscale of vulcanized compounds based on a natural rubber matrix reinforced with silica and/or carbon black is presented. Several compounds with different SiO2/CB ratios (1.5/1, 2.25/1, and 3/1) and total filler contents (55, 60, and 65 phr) were prepared and vulcanized at 150 °C. The experimental techniques used were rheometric, swelling and dynamic mechanical tests, and positron lifetime spectroscopy. From these techniques, cure reaction parameters, the fraction at the maximum degree of swelling, storage modulus, loss tangent, and fractional free volume were measured. Using a recent model based on a hydrodynamic description and the percolation of aggregates in a rubber matrix, it was found that regardless of the filler combinations, the dynamic storage modulus is well represented as a function of the filler volume fraction. Besides, beyond a critical SiO2/CB ratio (2.25/1) in the formulations of the compounds, the loss tangent does not depend on the SiO2/CB ratio. The results obtained show a direct correlation among mechanical properties, swelling and fractional free volume, and the type and amount of fillers in the reinforced compounds.