This study aimed to evaluate the time course and responsiveness of plasma interleukin-6 (IL-6) and creatine kinase (CK) levels following acute eccentric resistance exercise in sedentary obese older women with a different muscle quality index (MQI). Eighty-eight participants (69.4 ± 6.06 years) completed an acute eccentric resistance exercise (7 sets of 10 repetitions at 110% of 10-repetition maximum with 3 min rest interval). Participants were divided into two groups: high or low MQI according to 50th percentile cut-off. The responsiveness was based on minimal clinical important difference. There were no differences between groups and time on IL-6 and CK levels (p > 0.05). However, the high MQI group displayed a lower proportion of low responders (1 for laboratory and 2 for field-based vs. 5 and 4) and a higher proportion of high responders for IL-6 (7 for laboratory and 6 for field-based vs. 4 and 5) compared to low MQI group. In addition, the high MQI group showed a higher proportion of high responders for CK (11 for laboratory and 9 for field-based vs. 6 and 6) compared to low MQI. A prior MQI screening can provide feedback to understand the magnitude response. Individual responsiveness should be taken into consideration for maximizing eccentric exercise prescription.