A mass based phylonumerics approach is shown to be able to investigate the origins of the emergence of antiviral resistance mutations in influenza neuraminidase through a global view of mutational trends. Frequent ancestral and descendant mutations that precede and follow the manifestation of antiviral resistance mutations are identified in N2 neuraminidase. The majority occur in the head region around the active site and drive hydrophilicity changes, primarily through the incorporation or loss of hydroxyl groups. These increase or reduce the accessibility of the site to the bulk solvent. The most frequent ancestral mutations that occur on at least two occasions are I/L307M, G/A414S/T, I312T, I/L307S, P386S and S367N; the latter introducing a glycosylation site. The most frequent descendant mutation, after incorporation of an antiviral resistance mutation, is D/E401G/A. Together with others observed, this restore the protein´s hydrophobicity about the active site region that limits entry of a sialic acid or inhibitor molecule and reduces viral fitness. The results of this global in silico phylonumerics study demonstrate that evolutionary mechanisms and functionally linked or compensatory mutations, remote in the sequence or structure, can be identified and interrogated at a molecular level.