The need for structural materials with high-temperature strength and oxidation resistance coupled with adequate lower-temperature toughness for potential use at temperatures above ∼1000 °C has remained a persistent challenge in materials science. In this work, one promising class of intermetallic alloys is examined, namely, boron-containing molybdenum silicides, with compositions in the range Mo (bal), 12 to 17 at. pct Si, 8.5 at. pct B, processed using both ingot (I/M) and powder (P/M) metallurgy methods. Specifically, the oxidation (“pesting”), fracture toughness, and fatigue-crack propagation resistance of four such alloys, which consisted of ∼21 to 38 vol. pct α-Mo phase in an intermetallic matrix of Mo3Si and Mo5SiB2 (T2), were characterized at temperatures between 25 °C and 1300 °C. The boron additions were found to confer improved “pest” resistance (at 400 °C to 900 °C) as compared to unmodified molybdenum silicides, such as Mo5Si3. Moreover, although the fracture and fatigue properties of the finer-scale P/M alloys were only marginally better than those of MoSi2, for the I/M processed microstructures with coarse distributions of the α-Mo phase, fracture toughness properties were far superior, rising from values above 7 MPa √m at ambient temperatures to almost 12 MPa √m at 1300 °C. Similarly, the fatigue-crack propagation resistance was significantly better than that of MoSi2, with fatigue threshold values roughly 70 pct of the toughness, i.e., rising from over 5 MPa √m at 25 °C to ∼8 MPa √m at 1300 °C. These results, in particular, that the toughness and cyclic crack-growth resistance actually increased with increasing temperature, are discussed in terms of the salient mechanisms of toughening in Mo-Si-B alloys and the specific role of microstructure.