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Simple Summary: Treatment of relapsed or metastatic rhabdomyosarcoma (RMS) has low survival rates due to resistance mechanisms. In this work, experiments were undertaken to identify potential druggable pathways involved in radiotherapy resistance. We found that prolonged activation of a protein network formed by Akt1, Src, and caveolin-1 (Cav1) lowers intracellular reactive oxygen species (ROS) levels through the acquisition of high catalase expression, conferring radioresistance to RMS cells. Treatment of radioresistant cells with statins, drugs used worldwide for the treatment of hypercholesterolemia, significantly attenuated the Akt1/Cav1 signaling and radioresistance mechanisms through increased cell apoptosis. This evidence suggests that administration of statins could help to improve the success of radiotherapy in RMS. Identifying the molecular mechanisms underlying radioresistance is a priority for the treatment of RMS, a myogenic tumor accounting for approximately 50% of all pediatric soft tissue sarcomas. We found that irradiation (IR) transiently increased phosphorylation of Akt1, Src, and Cav1 in human RD and RH30 lines. Synthetic inhibition of Akt1 and Src phosphorylation increased ROS levels in all RMS lines, promoting cellular radiosensitization. Accordingly, the elevated activation of the Akt1/Src/Cav1 pathway, as detected in two RD lines characterized by overexpression of a myristoylated Akt1 form (myrAkt1) or Cav1 (RDCav1), was correlated with reduced levels of ROS, higher expression of catalase, and increased radioresistance. We found that treatment with cholesterol-lowering drugs such as lovastatin and simvastatin promoted cell apoptosis in all RMS lines by reducing Akt1 and Cav1 levels and increasing intracellular ROS levels. Combining statins with IR significantly increased DNA damage and cell apoptosis as assessed by γ histone 2AX (γH2AX) staining and FACS analysis. Furthermore, in combination with the chemotherapeutic agent actinomycin D, statins were effective in reducing cell survival through increased apoptosis. Taken together, our findings suggest that the molecularly linked signature formed by Akt1, Src, Cav1, and catalase may represent a prognostic determinant for identifying subgroups of RMS patients with higher probability of recurrence after radiotherapy. Furthermore, statin-induced oxidative stress could represent a treatment option to improve the success of radiotherapy. [ABSTRACT FROM AUTHOR]