Background and Purpose: The dual inhibition of thioredoxin reductase (TrxR) and glutathione reductase (GSHR) has emerged as a promising approach for the treatment of cancer and for promoting the defense mechanism by the immune system. In a previous report, we described a modular and novel strategy for the synthesis of a small molecule library. Here, we aim to discover a novel benzopyrane derivative that possesses a multitarget anticancer mechanism of action. Experimental Approach: The anticancer effect of SIMR1281 was evaluated in vitro to determine its effect on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and induction of apoptois. In addition, SIMR1281 was evaluated in vivo for its safety and in xenograft mice model. Key Results: SIMR1281 strongly inhibits GSHR while moderately inhibits TrxR. It inhibits cell proliferation of various cancers and mediates the induction of DNA damage machinery. SIMR1281, perturbs cell cycle, inactivates Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induces apoptosis and strongly attenuates cell survival machinery. SIMR1281 significantly reduces tumor volume in a xenograft model while maintaining a high in vivo safety profile. Conclusion and Implications: Our findings demonestrate that SIMR1281 possesses a promising multitarget anticancer activity in vitro and in vivo against multiple types of cancers while maintaining a high in vivo safety profile. This unique activity of SIMR1281 represents an innovative strategy for the treatment of various types of cancers and places this compound in a privileged position as a potential clinical drug candidate.