Objective To examine whether Massachusetts (MA) health reform affected substance (alcohol or drug) use disorder (SUD)–related hospitalizations in acute care hospitals. Data/Study Setting 2004–2010 MA inpatient discharge data. Design Difference‐in‐differences analysis to identify pre‐ to postreform changes in age‐ and sex‐standardized population‐based rates of SUD‐related medical and surgical hospitalizations, adjusting for secular trends. Data Extraction Methods We identified 373,751 discharges where a SUD‐related diagnosis was a primary or secondary discharge diagnosis. Findings Adjusted for age and sex, the rates of drug use–related and alcohol use–related hospitalizations prereform were 7.21 and 8.87 (per 1,000 population), respectively, in high‐uninsurance counties, and 8.58 and 9.63, respectively, in low‐uninsurance counties. Both SUD‐related rates increased after health reform in high‐ and low‐uninsurance counties. Adjusting for secular trends in the high‐ and low‐uninsurance counties, health reform was associated with no change in drug‐ or alcohol‐related hospitalizations. Conclusions Massachusetts health reform was not associated with any changes in substance use disorder–related hospitalizations. Further research is needed to determine how to reduce substance use disorder–related hospitalizations, beyond expanding insurance coverage.