In grassland ecosystems, it is well known that increasing plant species diversity can improve ecosystem functions (i.e., ecosystem responses), for example, by increasing productivity and reducing weed invasion. Diversity-Interactions models use species proportions and their interactions as predictors in a regression framework to assess biodiversity and ecosystem function relationships. However, it can be difficult to model numerous interactions if there are many species, and interactions may be temporally variable or dependent on spatial planting patterns. We developed a new Diversity-Interactions mixed model for jointly assessing many species interactions and within-plot species planting pattern over multiple years. We model pairwise interactions using a small number of fixed parameters that incorporate spatial effects and supplement this by including all pairwise interaction variables as random effects, each constrained to have the same variance within each year. The random effects are indexed by pairs of species within plots rather than a plot-level factor as is typical in mixed models, and capture remaining variation due to pairwise species interactions parsimoniously. We apply our novel methodology to three years of weed invasion data from a 16-species grassland experiment that manipulated plant species diversity and spatial planting pattern and test its statistical properties in a simulation study.Supplementary materials accompanying this paper appear online. Supplementary materials for this article are available at 10.1007/s13253-022-00505-2.