Professor Semenza was a faculty member at UC Berkeley, UC Irvine, Oregon Health and Science University, and at Portland State University where he taught in the Oregon Masters Program of Public Health. He has worked internationally with WHO, CDC, and USAID in countries such as Uzbekistan, Sudan, Egypt, Brazil, and Haiti.

His interest in reducing climate risks for society at large, extents back almost 20 years; in July 1995, he led the CDC response to a record-breaking heat wave that killed more than 700 people in Chicago. The findings of this study were immediately incorporated into climate change adaptation policies for metropolitan areas. He has also examined the health risks from coastal water contamination due to heavy precipitation events linked with climate change.

He is currently working on environmental and climatic drivers of vector-borne and water-borne disease transmission in Europe; for example, the 2010 heat waves in south-eastern Europe that gave rise to large West Nile fever outbreaks or the environmental suitability of malaria transmission in Greece. He has also worked on urban sustainability and community resilience in metropolitan areas suffering from urban blight. Through community outreach and engagement he was able to implement environmental interventions that advanced social capital and community wellbeing.