Farming animals that are resilient to various instabilities could improve both animal welfare and system sustainability. We evaluated three resilience indicators (Var, LnVar, and r-auto) in Holstein cattle on Czech farms using a bio-economic approach. We considered 3655 cows based on their genetic predisposition as 25% most resilient (Q3), median (Q2), and 25% least resilient (Q1), as well as their performance characteristics from routine production testing. Most of the performance characteristics significantly differed (p < 0.05) among the defined resilience quartiles. Q3 cows had slightly lower milk yield, higher milk component content, better udder health, and shorter dry periods compared to Q2 cows. The longevity of Q3 cows differed according to the indicator used (this was higher in Var and LnVar, but lower in r-auto). The highest profitability was found for the Q2 group in Var and r-auto and for Q1 in LnVar. Across all three resilience indicators, Q3 cows were the least profitable. Milk yield, lactation persistence, longevity, and milk fat and protein content contributed most to farm profit change across the resilience groups. The generality and simulation accuracy confirmed that the bio-economic model is suitable for the comprehensive setting and economic evaluation of resilience indicators and cattle performance.