San Cristóbal volcano in northwest Nicaragua is one of the most active basaltic–andesitic stratovolcanoes of the Central American Volcanic Arc (CAVA). Here we provide novel constraints on the volcano's magmatic plumbing system, by presenting the first direct measurements of major volatile contents in mafic-to-intermediate glass inclusions from Holocene and historic-present volcanic activity. Olivine-hosted (forsterite [Fo] < 80; Fo< 80) glass inclusions from Holocene tephra layers contain moderate amounts of H2O (0.1–3.3 wt%) and S and Cl up to 2500 μg/g, and define the mafic (basaltic) endmember component. Historic-present scoriae and tephra layers exhibit more-evolved olivines (Fo69–72) that contain distinctly lower volatile contents (0.1–2.2 wt% H2O, 760–1675 μg/g S, and 1021–1970 μg/g Cl), and represent a more-evolved basaltic–andesitic magma. All glass inclusions are relatively poor in CO2, with contents reaching 527 μg/g (as measured by nanoscale secondary ion mass spectrometry), suggesting pre- to postentrapment CO2 loss to a magmatic vapor. We use results of Raman spectroscopy obtained in a population of small (< 50 μm) inclusions with CO2-bearing shrinkage bubbles (3–12 μm) to correct for postentrapment CO2 loss to bubbles, and to estimate the original minimum CO2 content in San Cristóbal parental melts at ~ 1889 μg/g, which is consistent with the less-CO2-degassed melt inclusions (MI) (> 1500 μg/g) found in Nicaragua at Cerro Negro, Nejapa, and Granada. Models of H2O and CO2 solubilities constrain the degassing pathway of magmas up to 425 MPa (~ 16 km depth), which includes a deep CO2 degassing step (only partially preserved in the MI record), followed by coupled degassing of H2O and S plus crystal fractionation at magma volatile saturation pressures from ∼ 195 to < 10 MPa. The variation in volatile contents from San Cristóbal MI is interpreted to reflect (1) Holocene eruptive cycles characterized by the rapid emplacement of basaltic magma batches, saturated in volatiles, at depths of 3.8–7.4 km, and (2) the ascent of more-differentiated and cogenetic volatile-poor basaltic andesites during historic-present eruptions, having longer residence times in the shallowest (< 3.4 km) and hence coolest regions of the magmatic plumbing system. We also report the first measurements of the compositions of noble-gas isotopes (He, Ne, and Ar) in fluid inclusions in olivine and pyroxene crystals. While the measured 40Ar/36Ar ratios (300–304) and 4He/20Ne ratios (9–373) indicate some degree of air contamination, the 3He/4He ratios (7.01–7.20 Ra) support a common mantle source for Holocene basalts and historic-present basaltic andesites. The magmatic source is interpreted as generated by a primitive MORB-like mantle, that is influenced to variable extents by distinct slab fluid components for basalts (Ba/La ~ 76 and U/Th ~ 0.8) and basaltic andesites (Ba/La ~ 86 and U/Th ~ 1.0) in addition to effects of magma differentiation. These values for the geochemical markers are particularly high, and their correlation with strong plume CO2/S ratios from San Cristóbal is highly consistent with volatile recycling at the CAVA subduction zone, where sediment involvement in mantle fluids influences the typical relatively C-rich signature of volcanic gases in Nicaragua.