This study analyzed the acute and time-course changes following one resistance training (RT) set (1SET) and three sets (3SET) on hemodynamic and physical performance parameters in individuals with different cognitive impairment levels. Thirty-nine individuals (22 women and 17 men aged 80 ± 9 years) grouped by cognitive impairment (mild [MILD], moderate [MOD], and severe [SEV]) randomly performed two protocols, each separated by one week, of 1SET or 3SET of 10 repetitions. Before (PRE), immediately (POST), and 72 h after (POST72) protocols, the participants performed the following measurements: systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), 1-kg medicine ball throw (MBT) distance, five-repetition sit-to-stand (STS) time, and handgrip strength (HGS). A three-way ANOVA with repeated measures revealed no significant differences between 1SET and 3SET on SBP, DBP, HR, STS, MBT, and HGS in any group at any time (all p ≥ 0.05). SEV increased SBP and HR from PRE to POST and decreased STS time after 3SET. From POST to POST72, all groups decreased SBP after both protocols, and SEV improved STS time after 3SET and HGS following both protocols. Furthermore, from PRE to POST72, MILD decreased SBP, while SEV improved HGS following 1SET and STS time following 3SET. These findings demonstrate that single and multiple sets cause acute hemodynamic changes, with a tendency to reduce SBP within 72 h. Additionally, individuals with worse cognitive function showed greater adaptive responses over time in physical performance, with 1SET improving HGS and 3SET enhancing STS performance. Trial registration: ClinicalTrials.gov ID: NCT06185010.