Background Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography. Methods We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)‐by‐drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community‐based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE‐Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta‐analyses of main effects of drugs and 2.5 million SNP‐by‐drug interaction estimates. Results We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE‐Is with consistent effects across cohorts (smallest p = 4.7 × 10−8, minor allele frequency range 0.09–0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population. Conclusions Our study identified one locus having genome‐wide significant SNP‐by‐drug interaction effect on RWT among dCCB users in comparison to ACE‐I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment. This study highlights the potential impact of antihypertensive treatments as well as their pharmacogenetic effect of on left ventricular (LV) traits in African Americans among 2,068 participants across five community‐based cohorts. Dihydropyridine calcium channel blocker (dCCB) use was observed to be associated with greater LV mass than thiazide diuretic use. A single locus on chromosome 20 was also identified to modify the association between relative wall thickness and treatment when comparing dCCBs to angiotensin converting enzyme inhibitors with consistent effects across cohorts.