A tissue's microstructure determines its failure properties at larger length scales, however, the specific relationship between microstructure and macroscopic failure in native and engineered soft tissues (such as capsular ligaments, aortic aneurysms, or vascular grafts) has proven elusive. In this study, variations in the microscale fiber alignment in collagen gel tissue analogs were modeled in order to understand their effects on macroscale damage and failure outcomes. The study employed a multiscale finite-element (FE) model for damage and failure in collagen-based materials. The model relied on microstructural representative volume elements (RVEs) that consisted of stochastically-generated networks of discrete type-I collagen fibers. Fiber alignment was varied within RVEs and between layers of RVEs in a macroscopic FE model of a notched dogbone geometry. The macroscale stretch and the microscale response of fibers for each of the differently aligned cases were compared as the dogbone was uniaxially extended to failure. Networks with greater fiber alignment parallel to the direction of extension failed at smaller strains (with a 6–22% reduction in the Green strain at failure), however, at greater grip forces (a 28–60% increase) than networks with fibers aligned perpendicular to the extension. Alternating layers of crisscrossed network alignments (aligned ±45 deg to the direction of extension) failed at smaller strains but at greater grip forces than those created using one fiber alignment type. In summary, variations in microscale structure via fiber alignment produced different macroscale failure trends. To conclude, these findings may be significant in the realm of tissue engineering and in soft tissue biomechanics.