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Abstract As the next generation of large galaxy surveys come online, it is becoming increasingly important to develop and understand the machine-learning tools that analyze big astronomical data. Neural networks are powerful and capable of probing deep patterns in data, but they must be trained carefully on large and representative data sets. We present a new “hump” of the Cosmology and Astrophysics with MachinE Learning Simulations (CAMELS) project: CAMELS-SAM, encompassing one thousand dark-matter-only simulations of (100h⁻¹cMpc)³with different cosmological parameters (Ω_mandσ₈) and run through the Santa Cruz semi-analytic model for galaxy formation over a broad range of astrophysical parameters. As a proof of concept for the power of this vast suite of simulated galaxies in a large volume and broad parameter space, we probe the power of simple clustering summary statistics to marginalize over astrophysics and constrain cosmology using neural networks. We use the two-point correlation, count-in-cells, and void probability functions, and we probe nonlinear and linear scales across 0.68 <R<27h⁻¹cMpc. We find our neural networks can both marginalize over the uncertainties in astrophysics to constrain cosmology to 3%–8% error across various types of galaxy selections, while simultaneously learning about the SC-SAM astrophysical parameters. This work encompasses vital first steps toward creating algorithms able to marginalize over the uncertainties in our galaxy formation models and measure the underlying cosmology of our Universe. CAMELS-SAM has been publicly released alongside the rest of CAMELS, and it offers great potential to many applications of machine learning in astrophysics:https://camels-sam.readthedocs.io.