Objectives: The diverse list of tasks and needs related to the SARS-CoV-2 pandemic may lead to different professional experiences in nurses working with patients infected with and not infected with SARS-CoV-2. The aim of the study was to measure the professional challenges of nurses working during the SARS-CoV-2 pandemic in Poland. Material and Methods: The study was conducted in 2021 in a group of 151 nurses. The following scales were used: the Perceived Stress Scale (PSS-10), the General Self-Efficacy Scale (GSES), the Impact of Event Scale – Revised (IES-R), the Minnesota Satisfaction Questionnaire (MSQ-SF), the Areas of Worklife Survey (AWS) and the Maslach Burnout Inventory – Human Services Survey (MBIHSS). Results: Nurses working with patients infected with SARS-CoV-2 showed a positive correlation between workload and emotional exhaustion (ρ = 0.26, p = 0.02), as well as positive correlations among control, community and depersonalization (ρ = 0.25, p = 0.02; ρ = 0.23, p = 0.04). Among nurses working with uninfected patients, positive correlations were found among control, community, fairness and emotional exhaustion (ρ = 0.40, p = 0.000; ρ = 0.41, p = 0.000; ρ = 0.25, p = 0.03), as well as correlations between control and depersonalization (ρ = 0.33, p = 0.01), and among control, community and personal accomplishment (ρ = 0.23, p = 0.05; ρ = 0.27, p = 0.02). Conclusions: Nurses working during the SARS-CoV-2 pandemic with infected and uninfected patients both experienced a variety of psychosocial challenges in coping with the demands of their work, social relationships and personal life. Int J Occup Med Environ Health. 2023;36(1):112–24