Objectives This study aimed to investigate the technostress creators and outcomes among University medical and nursing faculties and students as direct effects of the remote working environment during the COVID-19 pandemic. Background Due to the current COVID-19 pandemic, shifting to virtual learning that implies utilizing the information and communication technologies (ICTs) is urgent. Technostress is a problem commonly arising in the virtual working environments and it occurs due to misfitting and maladaptation between the individual and the changeable requirements of ICTs. Methods A multicenter cross-sectional study was conducted in medicine and nursing colleges of 5 Egyptian universities and included both staff members and students. The data were collected through personal interviews, from January to May 2021. All the participants took a four-part questionnaire that asked about personal and demographic data, technostress creators, job or study, and technical characteristics and technostress outcomes (burnout, strain, and work engagement). Furthermore, participants' blood cortisol and co-enzyme Q10 (CoQ10) levels were tested in a random sample of the students and medical staff. Results A total of 3,582 respondents participated in the study, 1,056 staff members and 2,526 students where 33.3% of the staff members and 7.6% of students reported high technostress. Among staff members, total technostress score significantly predicted Cortisol level (β = 2.98, CI 95%: 0.13-5.83), CoQ10(β = −6.54, CI 95%: [(−8.52)–(−4.56), strain (β = 1.20, CI 95%: 0.93–1.47), burnout (β = 0.73, CI 95%: 0.48–0.97) and engagement (β = −0.44, CI 95%: [(−0.77)–(−0.11)]) whereas among students, total technostress score significantly predicted cortisol level (β = 6.64, CI 95%: 2.78–10.49), strain (β = 1.25, CI 95%: 0.72–1.77), and burnout (β = 0.70, CI 95%: 0.37–1.04). Among staff members and students, technology characteristics were significantly positive predictors to technostress while job characteristics were significantly negative predictors to technostress. Conclusion The Egyptian medical staff members and students reported moderate-to-high technostress which was associated with high burnout, strain, and cortisol level; moreover, high technostress was associated with low-work engagement and low CoQ10 enzyme. This study highlighted the need to establish psychological support programs for staff members and students during the COVID-19 pandemic.