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Maintaining adequate liquidity while preserving profitability remains a central challenge for commercial banks because liquid assets strengthen resilience but typically generate lower returns than loans and other earning assets. This study investigates the effect of liquidity on the profitability of U.S. commercial banks using 8,000 quarterly bank observations for 2010–2024. Profitability is measured by return on assets (ROA), with return on equity (ROE) used for robustness, while liquidity, capital adequacy, the loan-to-asset ratio, and bank size are modeled as explanatory variables. Pooled OLS, fixed-effects, and random-effects estimators are compared, and diagnostic tests support a two-way fixed-effects model with standard errors clustered by bank and quarter. The preferred estimates show that a one-percentage-point increase in the liquidity ratio reduces annualized ROA by 0.0183 percentage points (SE = 0.0031; p < 0.001). A one-standard-deviation rise in liquidity, equal to 5.52 percentage points, lowers ROA by approximately 0.101 percentage points, representing 9.2% of the sample mean ROA of 1.097%. Capital adequacy increases ROA by 0.0530 percentage points, and the loan-to-asset ratio increases it by 0.0148 percentage points, both at p < 0.001, whereas bank size is insignificant (β = 0.1008; p = 0.352). The ROE robustness model also yields a negative liquidity coefficient of −0.1074 (p < 0.001). The findings confirm a measurable liquidity–profitability trade-off and support risk-sensitive liquidity regulation that protects financial stability without encouraging persistently excessive holdings of low-yield liquid assets.