diff --git a/pkg/sql/opt/norm/reject_nulls_funcs.go b/pkg/sql/opt/norm/reject_nulls_funcs.go
index a368ea46246d..784681ab360a 100644
--- a/pkg/sql/opt/norm/reject_nulls_funcs.go
+++ b/pkg/sql/opt/norm/reject_nulls_funcs.go
@@ -214,9 +214,10 @@ func DeriveRejectNullCols(in memo.RelExpr, disabledRules intsets.Fast) opt.ColSe
 		relProps.Rule.RejectNullCols.UnionWith(deriveScanRejectNullCols(in))
 	}
 
-	if relProps.Rule.RejectNullCols.Intersects(relProps.NotNullCols) {
-		panic(errors.AssertionFailedf("null rejection requested on non-null column"))
-	}
+	// Don't attempt to request null-rejection for non-null cols. This can happen
+	// if normalization failed to null-reject, and then exploration "uncovered"
+	// the possibility for null-rejection of a column.
+	relProps.Rule.RejectNullCols.DifferenceWith(relProps.NotNullCols)
 
 	return relProps.Rule.RejectNullCols
 }
diff --git a/pkg/sql/opt/norm/testdata/rules/reject_nulls b/pkg/sql/opt/norm/testdata/rules/reject_nulls
index fc90b4046727..42fc00ddbcdf 100644
--- a/pkg/sql/opt/norm/testdata/rules/reject_nulls
+++ b/pkg/sql/opt/norm/testdata/rules/reject_nulls
@@ -1691,3 +1691,60 @@ project
       ├── 0 [as="?column?":66]
       ├── '23:43:20-08:00:00' [as="?column?":67]
       └── '2026-09-17 11:54:13.000946' [as=col_12038:68]
+
+# Regression test for #100559 - don't panic when exploration uncovers possible
+# null-rejection that normalization failed to find.
+exec-ddl
+CREATE TABLE t0_100559 (c0 INTERVAL);
+----
+
+exec-ddl
+CREATE TABLE t1_100559 (c0 INTERVAL);
+----
+
+exec-ddl
+CREATE TABLE t2_100559 (c0 FLOAT);
+----
+
+opt
+SELECT t1_100559.c0 AS c0 FROM t0_100559, t2_100559
+FULL OUTER JOIN t1_100559 ON true
+WHERE (
+  ((t0_100559.c0) IN (t1_100559.c0))
+  AND ((t2_100559.c0) IN (SELECT STDDEV(t2_100559.c0) FROM t2_100559))
+);
+----
+project
+ ├── columns: c0:9!null
+ └── inner-join (hash)
+      ├── columns: t0_100559.c0:1!null t2_100559.c0:5!null t1_100559.c0:9!null
+      ├── fd: (1)==(9), (9)==(1)
+      ├── right-join (cross)
+      │    ├── columns: t2_100559.c0:5!null t1_100559.c0:9
+      │    ├── scan t1_100559
+      │    │    └── columns: t1_100559.c0:9
+      │    ├── semi-join (hash)
+      │    │    ├── columns: t2_100559.c0:5!null
+      │    │    ├── select
+      │    │    │    ├── columns: t2_100559.c0:5!null
+      │    │    │    ├── scan t2_100559
+      │    │    │    │    └── columns: t2_100559.c0:5
+      │    │    │    └── filters
+      │    │    │         └── t2_100559.c0:5 IS NOT NULL [outer=(5), constraints=(/5: (/NULL - ]; tight)]
+      │    │    ├── scalar-group-by
+      │    │    │    ├── columns: stddev:17
+      │    │    │    ├── cardinality: [1 - 1]
+      │    │    │    ├── key: ()
+      │    │    │    ├── fd: ()-->(17)
+      │    │    │    ├── scan t2_100559
+      │    │    │    │    └── columns: t2_100559.c0:13
+      │    │    │    └── aggregations
+      │    │    │         └── std-dev [as=stddev:17, outer=(13)]
+      │    │    │              └── t2_100559.c0:13
+      │    │    └── filters
+      │    │         └── t2_100559.c0:5 = stddev:17 [outer=(5,17), constraints=(/5: (/NULL - ]; /17: (/NULL - ]), fd=(5)==(17), (17)==(5)]
+      │    └── filters (true)
+      ├── scan t0_100559
+      │    └── columns: t0_100559.c0:1
+      └── filters
+           └── t0_100559.c0:1 = t1_100559.c0:9 [outer=(1,9), constraints=(/1: (/NULL - ]; /9: (/NULL - ]), fd=(1)==(9), (9)==(1)]