Abstract Background Pancreatitis is an inflammatory disorder resulting from the autoactivation of trypsinogen in the pancreas. The genetic basis of the disease is an old phenomenon, and evidence is accumulating for the involvement of synonymous/non-synonymous codon variants in disease initiation and progression. Results The present study envisaged a panel of 26 genes involved in pancreatitis for their codon choices, compositional analysis, relative dinucleotide frequency, nucleotide disproportion, protein physical properties, gene expression, codon bias, and interrelated of all these factors. In this set of genes, gene length was positively correlated with nucleotide skews and codon usage bias. Codon usage of any gene is dependent upon its AT and GC component; however, AGG, CGT, and CGA encoding for Arg, TCG for Ser, GTC for Val, and CCA for Pro were independent of nucleotide compositions. In addition, Codon GTC showed a correlation with protein properties, isoelectric point, instability index, and frequency of basic amino acids. We also investigated the effect of various evolutionary forces in shaping the codon usage choices of genes. Conclusions This study will enable us to gain insight into the molecular signatures associated with the disease that might help identify more potential genes contributing to enhanced risk for pancreatitis. All the genes associated with pancreatitis are generally associated with physiological function, and mutations causing loss of function, over or under expression leads to an ailment. Therefore, the present study attempts to envisage the molecular signature in a group of genes that lead to pancreatitis in case of malfunction.