Objective <p>The co-administration of calcium channel blockers (CCB) and opioids is common in hypertensive patients undergoing cardiac surgery. This study aimed to investigate the association between combinations of CCB with different opioids and length of stay (LOS) in this population.</p> Methods <p>This retrospective study included 2,093 hypertensive adult patients who underwent cardiac surgery, drawn from the MIMIC-IV database. Potential covariates were systematically screened through univariate logistic regression and LASSO regression. Subsequently, generalized linear model (GLM) and multivariable logistic regression analyses were employed to evaluate the association between different CCB-opioids combinations and LOS. To further explore heterogeneity, subgroup analyses and interaction analyses were conducted.</p> Results <p>GLM revealed that the concomitant use of CCB with morphine (β = 4.354, 95%CI: 2.535–6.173), oxycodone (β = 2.418, 95%CI: 0.943–3.893), and tramadol (β = 2.382, 95%CI: 1.340–3.427) was significantly associated with prolonged LOS compared to CCB use alone. Notably, among these three opioid drugs, the CCB-oxycodone combination showed a robust association with prolonged hospital stay across the majority of adjusted logistic regression models. Subgroup analyses identified significant interaction effects (<i>P</i> for interaction &lt; 0.001), showing that the association between CCB-oxycodone and extending LOS was substantially stronger in patients undergoing valve surgery and those with a CCI score &gt; 5.</p> Conclusion <p>Co-administration of CCB and oxycodone is robustly associated with prolonged LOS in hypertensive cardiac surgery patients. These findings highlight the necessity of individualized analgesic strategies to mitigate drug interaction risks.</p>