We construct a canonical differential structure on the configuration space $Υ$ over a singular base space $X$ and with a general invariant measure $μ$ on $Υ$. We present an analytic structure on $Υ$, constructing a strongly local Dirichlet form $\mathcal E$ on $L^2(Υ, μ)$ for $μ$ in a large class of probability measures. We then investigate the geometric structure of the extended metric measure space $Υ$ endowed with the $L^2$-transportation extended distance $\mathsf{d}_Υ$ and with the measure $μ$. By establishing Rademacher- and Sobolev-to-Lipschitz-type properties for $\mathcal E$, we finally provide a complete identification of the analytic and the geometric structure -- the canonical differential structure induced on $Υ$ by $X$ and $μ$ -- showing that $\mathcal E$ coincides with the Cheeger energy of $(Υ,\mathsf{d}_Υ,μ)$ and that the intrinsic distance of $\mathcal E$ coincides with $\mathsf{d}_Υ$. The class of base spaces to which our results apply includes sub-Riemannian manifolds, RCD spaces, and path/loop spaces over Riemannian manifolds; as for $μ$ our results include quasi-Gibbs measures, in particular: Poisson measures, canonical Gibbs measures, as well as some determinantal/permanental point processes (sine$_β$, Airy$_β$, Bessel$_{α,β}$, Ginibre). A number of applications to interacting particle systems and infinite-dimensional metric measure geometry are also discussed. In particular, we prove the universality of the $L^2$-transportation distance $\mathsf{d}_Υ$ for the Varadhan short-time asymptotics for diffusions on $Υ$, regardless of the choice of $μ$. Many of our results are new even in the case of configuration spaces over Euclidean spaces.