Genetic and paratypic factors largely determine the functional state of piglets. Among these factors, stress induced by weaning from the sow plays a dominant role. Despite previous research, the physiological response to this stress remains poorly understood. Our study aimed to determine the characteristics of piglets' physiological responses to the stress caused by weaning. Three groups of animals were formed based on the severity of their stress response: Group I was stress-resistant, Group II was weakly responsive, and Group III was strongly responsive. Piglets in all groups exhibited a stress response, as indicated by changes in hematological and physiological parameters. These changes generally occurred within the limits of moderate stress on the body's functional reserves and remained close to the physiological norm. Compared to animals in group III, piglets in groups I and II showed better immune response parameters against the background of stress. The biochemical parameters of the blood serum did not differ significantly at the time of weaning. Still, four days after the stress, the differences between the groups became more noticeable, indicating a response to the “weaning crisis.” By the ninth day, a tendency toward stabilization was observed. Stress caused by weaning piglets from sows was accompanied by changes in immune activity indicators and deviations in physiological parameters, particularly body temperature, respiratory rate, and pulse. Intergroup differences were mainly recorded on the fourth day after weaning. Thus, these results can justify practical approaches to minimizing the negative effects of stress during weaning, maintaining physiological stability, and improving piglets' overall health.