The evolution of evidence and availability of Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines have enabled assessment of pharmacogenetic (PGx) actionability and clinical implementation. However, population-level actionability is not well-characterized. We leveraged the Alabama Genomic Health Initiative (AGHI) to evaluate population-level PGx actionability. Participants (>18 years), representing all 67 Alabama counties, were genotyped using the Illumina Global Screening array. Using CPIC guidelines, actionability was evaluated using (1) genotype data and genetic ancestry, (2) prescribing data, and (3) combined genotype and medication data. Of 6,331 participants, 4230 had genotype data and 3386 had genotype and prescription data (76% women; 76% White/18% Black [self-reported]). Genetic ancestry was concordant with self-reported race. For CPIC level A genes, 98.6% had an actionable genotype (99.4% Blacks/African; 98.5% White/European). With the exception of DPYD and CYP2C19, the prevalence of actionable genotypes by gene differed significantly by race. Based on prescribing, actionability was highest for CYP2D6 (70.9%), G6PD (54.1%), CYP2C19 (53.5%), and CYP2C9 (47.5%). Among participants prescribed atenolol, carvedilol, or metoprolol, ~ 50% had an actionable ADRB1 genotype, associated with decreased therapeutic response, with higher actionability among Blacks compared to Whites (62.5% vs. 47.4%; p < 0.0001). Based on both genotype and prescribing frequencies, no significant differences in actionability were observed between men and women. This statewide effort highlights PGx population-level impact to help optimize pharmacotherapy. Almost all Alabamians harbor an actionable genotype, and a significant proportion are prescribed affected medications. Statewide efforts, such as AGHI, lay the foundation for translational research and evaluate “real-world” outcomes of PGx.