Blood transfusion is considered a life-saver in health care settings, but could potentially pose as a risk factor for transmission of life-threatening viral infections, including HIV, HBsAg, HCV and Syphilis infections. This study was carried out to find out the prevalence and trends of HIV and Syphilis infections among blood donors in the Northern Region of Ghana. Blood screening data of blood donors recorded in blood transfusion centers in the Northern region between 2011 and 2015 were collected and analyzed anonymously. Screening results for HIV and Syphils infections were sorted and analyzed from a total of 198,229 blood donors in the region within the period under consideration. Majority of the donors were female and aged between 20-39 years. The overall seroprevalence rates of HIV and Syphilis were 30.77% (7319) and 27.78% (4893) respectively. The highest seroprevalence was found for HIV followed by Syphilis. These infections were more prevalent in female donors. Highest seroprevalence for both HIV and Syphilis was observed among donors in their youthful ages, i.e. between 20 to 49 years, while Syphilis seroprevalence increased with age. There exists a decreasing trend of transfusiontransmissible viral infections (i.e. HIV and Syphilis) in blood donations. This indicates that the Ghana National Blood Service mandate of ensuring the safety of blood supply has been successful. Even though available statistics show that the prevalence rates of viral infections detected during blood donations has reduced drastically, there is still more to be done, especially using robust and efficient techniques like polymerase chain reaction (PCR). This, the researchers think could guarantee more safety blood for transfusion.