The objective of this study was to explore single nucleotide polymorphisms (SNPs), gene expression and economic evaluation of parameters associated with mastitis susceptibility in Holstein and Brown Swiss dairy cows. Two hundred and forty Holstein and Brown Swiss dairy cows (120 cows of each breed) were used in this study. The investigated dairy cows in each breed were allocated into two equal-sized groups (60 cows each); mastitis tolerant and affected groups. PCR-DNA sequencing of SELL, ABCG2, SLC11A1, FEZL, SOD1, CAT, GPX1, and AhpC/TSA revealed nucleotide sequence variations in the form of SNPs associated with mastitis tolerance/susceptibility in investigated Holstein and Brown Swiss dairy cows. Levels of SELL, SLC11A1 and FEZL gene expression were significantly up-regulated in mastitic Holstein and Brown Swiss dairy cows than in tolerant ones. Meanwhile, ABCG2, SOD1, CAT, GPX1, and AhpC/TSA genes were significantly downregulated. Regarding the economic parameters, significant differences were recorded for net returns and a reduction in the percentage of net profit, as the higher values of net returns were recorded for tolerant dairy cows than mastitic ones in both breeds; moreover, the net profit was reduced by 39% and 27% in mastitic Holstein and Brown Swiss dairy cows, respectively, when compared to tolerant ones. The results herein confirmed the potential significance of investigated genes as candidates for mastitis tolerance/susceptibility in Holstein and Brown Swiss dairy cows. Mastitis also has detrimental impacts on economic efficiency in dairy farms.