α-MnSe crystals as green and cost-efficient peroxidase mimics were successfully synthesized via a facial hydrothermal route in a glycerol/water solution system. They were first found to catalyze the reaction of peroxidase substrate 3,3′,5,5′-tetramethylbenzidine (TMB) in the presence of H2O2 to induce a blue color change, indicating an intrinsic peroxidase-like activity. The steady-state kinetic analysis showed that α-MnSe crystals had higher affinity for TMB and lower affinity for H2O2 compared with horseradish peroxidase. The crystal structure, morphology, and catalytic activity could be tailored by adjusting the starting raw materials. The usage of sodium dodecyl sulfate and glycerol could decrease the particle size of α-MnSe crystals to enhance the peroxidase-like activity. Furthermore, benefiting from the chemical and crystal stability, α-MnSe crystals have two potential advantages: long-term stability and ease of recovery, and thus have potential applications as a peroxidase mimic in chemical/bio detection.