Spinal manipulative therapy (SMT) is a common nonpharmacological treatment for low back pain (LBP). Although generally supported by systematic reviews and practice guidelines, clinical trials evaluating SMT have been characterized by small effect sizes. This study adopts a Multiphase Optimization Strategy framework to examine individual components of an SMT delivery protocol using a single-blind trial with the goal of identifying and optimizing a multicomponent SMT protocol. We enrolled 241 participants with LBP. All participants received 2 SMT treatment sessions in the first week then were randomly assigned additional treatment based on a fully factorial design. The 3 randomized treatment components provided in twice weekly sessions over 3 weeks were multifidus activating exercise, spinal mobilizing exercise, and additional SMT dose. Primary outcomes included clinical (Oswestry Disability Index, numeric pain intensity rating) and mechanistic (spinal stiffness, multifidus muscle activation) measures assessed at baseline, 1, 4, and 12 weeks. Significant differences were found for the Oswestry index after 12 weeks for participants receiving multifidus activating exercise (mean difference = -3.62, 97.5% CI: -6.89, -0.35; P= .01). There were no additional significant main or interaction effects for other treatment components or different outcome measures. The optimized SMT protocol identified in this study included SMT sessions followed by multifidus activating exercises. PERSPECTIVE: Optimizing the effects of nonpharmacological treatments such as SMT for LBP is challenging due to uncertainty regarding mechanisms and the complexity of multicomponent protocols. This factorial randomized trial examined SMT protocols provided with differing co-interventions with mechanistic and patient-centered outcomes. Patient-centered outcomes were optimized by inclusion of lumbar multifidus strengthening exercises.