We sought to evaluate the interaction between smoking status and operative approach following esophagectomy on perioperative outcomes. Patients undergoing esophagectomy for esophageal cancer were identified from the STS-GTSD Database between January 1, 2009 and December 31, 2022 and divided into six groups based on smoking status [never (NS), former (FS), current (CS)] and surgical approach [minimally invasive (MIE), open (OpenE)]. Primary outcomes were respiratory complications, operative mortality, major morbidity, and composite major morbidity and mortality. The final study population consisted of 27,373 (28.3% NS, 68.0% FS, and 13.7% CS) patients from 295 hospitals. Most cases were OpenE (58.1%), but the proportion of MIE increased from 19.2% in 2009 to 56.3% in 2022. Multivariable analysis showed: 1) risk-adjusted operative mortality was only decreased in never-smokers that underwent MIE (MIE-NS: AOR 0.61; CI: 0.45-0.82); 2) there were no significant differences in mortality among the groups compared to the reference OpenE-NS group. Respiratory complications, major morbidity, and composite mortality and morbidity outcomes showed similar smoking and surgical approach effects: 1) all outcomes were worse in smokers irrespective of approach; 2) within the same smoking status, AORs for respiratory complications and morbidity were slightly lower in MIE versus OpenE but these differences were non-significant. Respiratory complications and other major morbidity outcomes following esophagectomy are substantially worsened by smoking history particularly in current smokers. Among NS, MIE is associated with reduced operative mortality.