Objectives: This study aimed to assess the knowledge, attitude, and motivation toward stem cell donation among the Saudi population in Riyadh, Saudi Arabia. Methods: A cross-sectional study was conducted in Riyadh City using the visitors to randomly selected Malls according to the geographical distribution of Riyadh. A sample size of 800 participants was calculated and distributed equally in 5 different regions in Riyadh city. The participants were asked to complete a questionnaire that addressed their knowledge, attitude, and perception toward stem cell transplantation and donation. Results: Population knowledge about stem cell transplantation and donation is low. Only (37.8%) have enough information about stem cell transplantation and donation. There is a positive correlation between the level of education and participant’s knowledge regarding stem cell transplantation and donation. The increasing level of education was associated with a better understanding of stem cell donation and its role in therapy and saving lives. The study revealed that 39.3% of participants have willing for stem cell donation. The most common reason for not donating stem cells was the lack of information about stem cells and the value of the donation. Conclusion: Population knowledge about stem cell transplantation and donation needs to be increased to empower the willingness for stem cell donation. Probably a well-designed campaign for advocating stem cell donation becomes important in the country.