Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.