Background: Astrocytoma is a primary brain tumor arising from specific glial cells called astrocytes. Isocitrate dehydrogenase (IDH) mutations represent an early oncogenic event in glioma evolution. The 2-hydroxyglutarate builds up and is produced in grade II/III astrocytoma. Adjuvant chemo(radio)therapy is the standard treatment. Optimal treatment strategies are controversial due to the risk-benefit ratio. This study aimed to assess the effect of IDH mutation on the survival outcome with different treatment modalities for better understanding of the disease. Methods: Data were obtained from the SEER program for patients with diffuse and anaplastic astrocytoma diagnosed from 2018 to 2020. Patients were divided into wild-type (wIDH) and mutant-type (mIDH) groups and subclassified based on the received adjuvant therapy (chemotherapy, radiotherapy, chemoradiotherapy). All patients had surgery (tumor destruction, local excision, partial, radial, and total gross resection). SPSS 27 was used for statistical analysis, Kaplan–Meier curve, and Long-Rank test for survival analysis. Results: Out of 811 patients, 486 (59.9%) had mIDH, and 325 (40.1%) had wIDH. The 2-year relative survival for mIDH was 95% and 51% for wIDH, P < 0.001. The highest 2-year relative survival among the mIDH group was for patients who received adjuvant chemotherapy (100%), compared to adjuvant chemoradiotherapy (95.3%) and adjuvant radiotherapy (81.2%), P = 0.051. The 2-year survival for wIDH who received adjuvant chemotherapy, combined adjuvant chemoradiotherapy, and adjuvant radiotherapy were 66%, 51%, and 42%, respectively; P = 0.022. Conclusions: The mIDH had better 2-year relative survival compared to wIDH across all treatment modalities. Adjuvant chemotherapy had more than 20% survival benefit compared to radiotherapy in mIDH and wIDH. These results highlight adjuvant chemotherapy as the modality of choice for mIDH to improve the survival outcome and avoid radiotherapy’s unfavorable side effects. The study was registered at Clinicaltrial.gov with identification number of NCT06620926.