The Mars and Van Krevelen model can be applied to all the steps of the oxidation of isobutane by oxygen over a heteropolyanion catalyst. The reaction scheme includes both direct (from isobutane) and indirect (via methacrolein) methacrylic acid production. The determinant multiresponse criterion has proved very efficient in the simultaneous estimation of all parameters of this complex model which perfectly fits the measured partial pressures of isobutane, methacrolein, and methacrylic acid in a large range of experimental conditions. The reaction of isobutane with the oxidized sites is the rate-limiting step of the process. Temperature and the oxygen-to-hydrocarbon ratio do not affect selectivities for the main products. The methacrolein transformation is 50 times faster than the isobutane reaction but is a factor of degradation, whereas methacrylic acid is stable. To improve selectivity, the transformation from isobutane to methacrylic acid has to be favored. Moreover, a higher propensity of catalysts for hydrocarbon activation should increase productivity.