Background: Sickle cell anemia (SCD) is a relatively uncommon health condition in many countries, but it is prevalent in Saudi Arabia mainly due to the high incidence of consanguineous marriages. Regrettably, there are elevated rates of vaso-occlusive crises (VOCs) and blood transfusions, leading to poor quality of life and significant financial strain. Objective(s): This study aimed to assess the frequency of blood transfusions, out-of-pocket expenditures (OOPEs), and health-related quality of life (HRQoL) in SCD patients. Methods: This was a questionnaire-based cross-sectional study that involved SCD patients at a university-affiliated tertiary care center in Riyadh, Saudi Arabia. The patients’ medical and sociodemographic characteristics were obtained from the electronic medical records. Data on HRQoL and OOPEs were collected through a questionnaire-based interview. To present the baseline characteristics, descriptive statistics such as mean, standard deviation, frequency, and percentage were used. In addition, various statistical tests, including the Chi-Square test, Student t-test, one-way ANOVA, and multiple linear regression, were performed. Results: One hundred and eighteen patients consented to participate and were included in the analysis. Almost 53% of the patients were females. The mean age of the sample was 31 years, while the age-adjusted quality-adjusted life years (QALYs) was 24.33 years (p-value < 0.0001). Most patients (83.05%) reside in Riyadh with a monthly family income of less than USD 2666.67 (75.42%). Monthly OOPEs were, on average, USD 650.69 ± 1853.96, and one-third of the adult patients reported income loss due to illness, further exacerbating their financial strain. High frequency of blood transfusion (β = −0.0564, p-value = 0.0066) and higher number of comorbidities (β = −0.10367, p-value = 0.0244) were negatively associated with the HRQoL among adult patients. On the other hand, adult patients with higher levels of education had better HRQoL (β = 0.05378, p-value = 0.0377). Conclusions: The findings of this study highlight the negative impact of SCD on patients’ HRQoL and financial well-being. This underscores the urgent need for comprehensive systemic approaches to address the challenges posed by SCD in Saudi Arabia.