Defatted-sesame meal (DSM), a byproduct of sesame oil, has attracted considerable interest in the food industry because of its strong antioxidant activity. The aim of this study was to measure the content and distribution of lignans in DSM and evaluate their antioxidant activity after thermal processing and in vitro digestion. The results showed that the sesame lignans (SL) content and antioxidant activity were significantly influenced by the temperature and time during thermal preparation, and the maximum antioxidant potency composite index (ACI) was obtained after roasting the samples at 240 °C for 20 min. As sesame seed was processed with longer time and higher temperature, more pinoresinol diglucoside (PD) and sesamol were measured in DSM. According to the correlation matrix under thermal preparation, a significant contribution to the antioxidant potency of DSM was discovered. After in vitro digestion, the release amount of lignans increased by 19.6%, and the values of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and ACI gradually declined after digestion, with a 40% decrease in both the DPPH radical scavenging activity and the ACI from oral to intestinal phase. These results could be used to help improve the bioavailability of SL and obtaining high quality sesame byproducts.