diff --git a/tsdb/agent/series.go b/tsdb/agent/series.go
index f30ff96200..04c9f5fc39 100644
--- a/tsdb/agent/series.go
+++ b/tsdb/agent/series.go
@@ -93,6 +93,8 @@ type stripeSeries struct {
 	series []map[chunks.HeadSeriesRef]*memSeries
 	hashes []seriesHashmap
 	locks  []stripeLock
+
+	gcMut sync.Mutex
 }
 
 type stripeLock struct {
@@ -120,8 +122,14 @@ func newStripeSeries(stripeSize int) *stripeSeries {
 // GC garbage collects old series that have not received a sample after mint
 // and will fully delete them.
 func (s *stripeSeries) GC(mint int64) map[chunks.HeadSeriesRef]struct{} {
-	deleted := map[chunks.HeadSeriesRef]struct{}{}
+	// NOTE(rfratto): GC will grab two locks, one for the hash and the other for
+	// series. It's not valid for any other function to grab both locks,
+	// otherwise a deadlock might occur when running GC in parallel with
+	// appending.
+	s.gcMut.Lock()
+	defer s.gcMut.Unlock()
 
+	deleted := map[chunks.HeadSeriesRef]struct{}{}
 	for hashLock := 0; hashLock < s.size; hashLock++ {
 		s.locks[hashLock].Lock()
 
@@ -179,14 +187,17 @@ func (s *stripeSeries) Set(hash uint64, series *memSeries) {
 		hashLock = hash & uint64(s.size-1)
 		refLock  = uint64(series.ref) & uint64(s.size-1)
 	)
-	s.locks[hashLock].Lock()
-	defer s.locks[hashLock].Unlock()
 
-	if hashLock != refLock {
-		s.locks[refLock].Lock()
-		defer s.locks[refLock].Unlock()
-	}
-
-	s.hashes[hashLock].Set(hash, series)
+	// We can't hold both locks at once otherwise we might deadlock with a
+	// simulatenous call to GC.
+	//
+	// We update s.series first because GC expects anything in s.hashes to
+	// already exist in s.series.
+	s.locks[refLock].Lock()
 	s.series[refLock][series.ref] = series
+	s.locks[refLock].Unlock()
+
+	s.locks[hashLock].Lock()
+	s.hashes[hashLock].Set(hash, series)
+	s.locks[hashLock].Unlock()
 }
diff --git a/tsdb/agent/series_test.go b/tsdb/agent/series_test.go
new file mode 100644
index 0000000000..480f6c0263
--- /dev/null
+++ b/tsdb/agent/series_test.go
@@ -0,0 +1,76 @@
+// Copyright 2022 The Prometheus Authors
+// Licensed under the Apache License, Version 2.0 (the "License");
+// you may not use this file except in compliance with the License.
+// You may obtain a copy of the License at
+//
+// http://www.apache.org/licenses/LICENSE-2.0
+//
+// Unless required by applicable law or agreed to in writing, software
+// distributed under the License is distributed on an "AS IS" BASIS,
+// WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
+// See the License for the specific language governing permissions and
+// limitations under the License.
+
+package agent
+
+import (
+	"fmt"
+	"math"
+	"sync"
+	"testing"
+	"time"
+
+	"github.com/stretchr/testify/require"
+
+	"github.com/prometheus/prometheus/model/labels"
+	"github.com/prometheus/prometheus/tsdb/chunks"
+)
+
+func TestNoDeadlock(t *testing.T) {
+	const numWorkers = 1000
+
+	var (
+		wg           sync.WaitGroup
+		started      = make(chan struct{})
+		stripeSeries = newStripeSeries(3)
+	)
+
+	wg.Add(numWorkers)
+	for i := 0; i < numWorkers; i++ {
+		go func() {
+			defer wg.Done()
+			<-started
+			_ = stripeSeries.GC(math.MaxInt64)
+		}()
+	}
+
+	wg.Add(numWorkers)
+	for i := 0; i < numWorkers; i++ {
+		go func(i int) {
+			defer wg.Done()
+			<-started
+
+			series := &memSeries{
+				ref: chunks.HeadSeriesRef(i),
+				lset: labels.FromMap(map[string]string{
+					"id": fmt.Sprintf("%d", i),
+				}),
+			}
+			stripeSeries.Set(series.lset.Hash(), series)
+		}(i)
+	}
+
+	finished := make(chan struct{})
+	go func() {
+		wg.Wait()
+		close(finished)
+	}()
+
+	close(started)
+	select {
+	case <-finished:
+		return
+	case <-time.After(15 * time.Second):
+		require.FailNow(t, "deadlock detected")
+	}
+}