•Ca2+i in Df1/+ astrocytes was evaluated with Bayesian kinetic inference.•The activity of SERCA is altered in Df1/+ astrocytes.•Inhibition of SERCA in control astrocytes phenocopies Df1/+ astrocytes.•Altered activity of SERCA is a driver of calcium kinetics in Df1/+ astrocytes.•Bayesian kinetic inference is useful for mechanistic studies in astrocytes. Methods for deriving mechanistic information from intracellular calcium dynamics have largely been applied to neuronal data despite the knowledge of roles of glial cells in behavior, cognition, and psychiatric disorders. Using calcium imaging, computer vision, and Bayesian kinetic inference (BKI), we analyzed calcium dynamics in primary astrocytes derived from control or Df1/+ mice, a model of 22q11.2 deletion (DiGeorge syndrome). Inference of the highest-likelihood molecular kinetic characteristics of intracellular calcium dynamics identified changes in the activity of the sarcoendoplasmic reticulum calcium ATPase (SERCA). Application of a SERCA inhibitor to wild-type astrocytes reproduced the differences detected in Df1/+ astrocytes. Our work reveals the molecular changes driving the calcium kinetics in astrocytes from a 22q11.2 deletion model. BKI can be useful for mechanistically dissecting calcium dynamics in glial cells and formulating and testing hypotheses about underlying molecular mechanisms.