In order to improve the operational performance of the self-developed 4HLB-4 half-feed four-row peanut combine harvester, single-factor and multifactor field tests were conducted on key operational parameters affecting the quality of harvesting. The response surface methodology was used to study the effects of the forward speed, clamping height, peanut picking roller rotational speed, and cleaning sieve vibrational frequency on the loss rate and impurity rate. A response surface regression model of the loss rate and impurity rate was constructed. A multi-objective integrated optimization was carried out for each factor. The results showed that, in terms of the order of significance, the influence of each factor on the impurity rate was as follows: cleaning sieve vibrational frequency > clamping height > forward speed > peanut picking roller rotational speed. The order of significance of the influence of each factor on the loss rate was as follows: peanut picking roller rotational speed > forward speed > clamping height > cleaning sieve vibrational frequency. The optimal combination of parameters was a forward speed of 0.85 m/s, clamping height of 190 mm, peanut picking roller rotational speed of 550 rpm, and cleaning sieve vibrational frequency of 590 cpm. Under these conditions, the impurity rate of 2.62% and the loss rate of 2.05% were obtained, which effectively reduced the impurity rate and loss rate and met the quality requirements of Chinese peanut mechanized harvesting operations. The results of this study can provide a basis for the improvement and optimization of the 4HLB-4 half-feed four-row peanut combine harvester and the optimization of its operating parameters.