diff --git a/openmc/deplete/microxs.py b/openmc/deplete/microxs.py
index e351c923df..d7624955e8 100644
--- a/openmc/deplete/microxs.py
+++ b/openmc/deplete/microxs.py
@@ -356,13 +356,17 @@ class MicroXS:
             reactions = chain.reactions
         mts = [REACTION_MT[name] for name in reactions]
 
-        # Normalize multigroup flux
-        multigroup_flux = np.array(multigroup_flux)
-        multigroup_flux /= multigroup_flux.sum()
-
         # Create 3D array for microscopic cross sections
         microxs_arr = np.zeros((len(nuclides), len(mts), 1))
 
+        # If flux is zero, safely return zero cross sections
+        multigroup_flux = np.array(multigroup_flux)
+        if (flux_sum := multigroup_flux.sum()) == 0.0:
+            return cls(microxs_arr, nuclides, reactions)
+
+        # Normalize multigroup flux
+        multigroup_flux /= flux_sum
+
         # Compute microscopic cross sections within a temporary session
         with openmc.lib.TemporarySession(**init_kwargs):
             # For each nuclide and reaction, compute the flux-averaged xs
diff --git a/tests/unit_tests/test_deplete_microxs.py b/tests/unit_tests/test_deplete_microxs.py
index 073b3f162d..5762a8511b 100644
--- a/tests/unit_tests/test_deplete_microxs.py
+++ b/tests/unit_tests/test_deplete_microxs.py
@@ -111,3 +111,16 @@ def test_multigroup_flux_same():
         energies=energies, multigroup_flux=flux, chain_file=chain_file)
 
     assert microxs_4g.data == pytest.approx(microxs_2g.data)
+
+
+def test_microxs_zero_flux():
+    chain_file = Path(__file__).parents[1] / 'chain_simple.xml'
+
+    # Generate micro XS based on zero flux
+    energies = [0., 6.25e-1, 5.53e3, 8.21e5, 2.e7]
+    flux = [0.0, 0.0, 0.0, 0.0]
+    microxs = MicroXS.from_multigroup_flux(
+        energies=energies, multigroup_flux=flux, chain_file=chain_file)
+
+    # All microscopic cross sections should be zero
+    assert np.all(microxs.data == 0.0)