Introduction: Gap in knowledge and fear of infection with negative attitude towards human immuno-deficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) are common in different cities across Saudi Arabia. The objectives of this study were to determine knowledge and attitude regarding HIV/AIDS among general population in Hail, Northern city in Saudi Arabia. Material and methods: A cross-sectional study was conducted among general population of Hail, Northern city of Saudi Arabia. A total of 388 participants were selected through multi-stage cluster sampling from different districts of the city. A validated and structured questionnaire was used to determine the knowledge and attitude levels, and logistic regression analysis was applied to define the association of knowledge and attitude levels with sociodemographic characteristics. A p-value < 0.005 was considered statistically significant. Results: Out of 388 study participants, the majority presented inappropriate knowledge (42.5%) and negative attitude (54.4%). In univariate analysis, age group of 16-25 years and unmarried (OR: 1.93, 95% CI: 1.27-2.92%, p = 0.002; and OR: 1.90; 95% CI: 1.23-2.92%, p = 0.003, respectively) were significantly associated with inappropriate knowledge level. Age group of 16-25 years, unmarried, and female gender (OR: 2.54, 95% CI: 1.77-3.86.92%, p = 0.000; OR: 1.84, 95% CI: 1.22-2.76%, p = 0.003; and OR: 2.42; 95% CI: 1.56-3.74%, p = 0.000, respectively) were significantly associated with negative attitude towards HIV/AIDS. After adjustment of covariates, age group of 16-25 years and female gender (OR: 2.54, 95% CI: 1.25-5.14%, p = 0.009; and OR: 2.14, 95% CI: 1.56-3.30%, p = 0.001, respectively) were significantly associated with negative attitude toward HIV/AIDS. Conclusions: The present study found that general population had negative attitude toward HIV/AIDS. Extensive health education campaign should be provided to the vulnerable groups of the society for rationale control and management of HIV/AIDS.