Utilizing synthetically generated random variates and laboratory measurements, we document the inherent limitations of the conventional structure function approach in limited sample size settings. We demonstrate that an alternative approach, based on the principle of maximum likelihood, can provide nearly unbiased structure function estimates with far less uncertainty under such unfavorable conditions. The superiority of this approach over the conventional approach does not diminish even in the case of strongly correlated samples. Two entirely different types of probability distributions, which have been reported in the turbulence literature, are found to be compatible with the proposed approach.