Acid mine drainage (AMD) is a phenomenon that occurs when pyrite that is present in abandoned coal mines comes in contact with oxygen and water, which results in the formation of sulfuric acid and iron hydroxide. Grouting of an abandoned mine with alkaline materials provides a permanent reduction in acid production. This study investigates the success of coal combustion by-product (CCB)-based grout mixtures in reducing AMD. The laboratory phase included testing of grouts with different proportions of Class F fly ash, flue gas desulfurization by-product, fluidized bed combustion by-product, and quicklime, for slump, modified flow, bleed, and strength. Then the selected optimal grout mixture was injected into the Frazee mine, located in Western Maryland. Pre- and post-injection water quality data were collected to assess the long-term success of the grouting operation by analyzing mine water, surface water, and groundwater. Laboratory tests indicated that the four mechanical properties of grout mixtures, slump, modified flow, bleed, and strength, are related to the fly ash and free lime contents of the mixture. Eight years of post-injection water quality monitoring shows that there has been a significant decrease in acidity, concentrations of major ions, and trace elements in the mine water. The groundwater and surface water data suggested no adverse impacts of AMD in the pre- or post-injection period. Tests performed on the field exhumed grout cores showed that the hardened grout retained its strength and low hydraulic conductivity with no evidence of in situ weathering. Overall, the results indicated that CCB-based grouts can control the acid mine drainage. However, the mechanical properties of the grout are highly critical for the construction phase, and long-term monitoring is essential for evaluating the effectiveness of the grouting process.