During the Polish campaign, he saw service in the Army before transferring to the Luftwaffe and undergoing fighter pilot training in 1940. Schiess was posted to the Geschwaderstab (Headquarters) of Jagdgeschwader 53, based on the Channel front in March 1941, then served, from December 1941, as Geschwader Adjutant. Staying there for nearly two years, he established a close friendship with the Geschwaderkommodore (wing commander) Günther Freiherr von Maltzahn.

On 22 June 1941, the opening day of Operation Barbarossa, Schiess scored his first victories destroying an I-153 biplane fighter and an Ilyushin DB-3 bomber. The members of his Staffel called him "Nawratil", after his radio call sign name.

After achieving 14 kills on the Eastern Front he was withdrawn in August, along with the rest of JG 53 and, following rest and refitting in Germany, then deployed in December to the Mediterranean. Operating from Sicily, Schiess flew sorties over Malta scoring 11 victories. Throughout 1942, and re-equipped with the new Bf 109G-2, he outscored his Geschwaderkommodore. In November, the Stab flight itself transferred to Tunisia, where Schiess continued his success, gaining a further 13 victories, including a B-17 four-engined bomber on 29 January 1943.

Leutnant Schiess was awarded the German Cross in Gold (Deutsches Kreuz in Gold) on 23 January 1943 as a member of Stab/JG 53. On 16 February 1943, the now Oberleutnant Schiess was appointed Staffelkapitän (squadron leader) of 8./JG 53. He was regarded as one of the most enthusiastic and aggressive pilots in the Mediterranean theatre, and often flew the escort missions for the Ju 52 transports as they tried to evacuate personnel out of Africa. On 18 April he shot down a Spitfire (for his 43rd victory), but nevertheless 24 heavy-laden transports were shot down and a further 35 damaged, in what became known as the "Palm Sunday Massacre".

Even when his unit was evacuated back to Sicily after the fall of Tunis in April 1943, he still flew over to Tunisia each day doing combat missions before returning to Sicily each night, writing home of "wonderful aerial combats". He went on to score 29 victories as leader of 8./JG 53 and reached 50 kills shooting down a P-38 over the sea south of Sicily on 21 May. Schiess was awarded the Knight's Cross on 21 June for 55 victories and then was sent on leave for 2 months, thereby missing the air battles over the invasion of Sicily. Returning to 8./JG 53 in mid-August, his unit was now flying out of southern Italy against the Allies, who were mounting a concerted campaign to destroy the transport net prior to an invasion of the Italian mainland. Schiess shot down 12 enemy aircraft in 11 days, of which seven were P-38 twin-engine fighters. Together with Jürgen Harder of III./JG 53, Schiess was promoted to the rank of Hauptmann on September 1, 1943.

The next day, on 2 September 1943, Schiess led a scramble against a USAAF B-25 bomber formation attacking rail marshalling yards at Cancello, Naples. His unit engaged the fighter escort of P-38 Lightnings. Unable to break through the fighter screen to attack the bombers, he followed the force back over the Gulf of Salerno. His final battle took place over the island of Ischia; at around 1:45PM, the pilots heard Franz Schiess radio: "At them again, everyone get ready!" At the time, the formation was 30 to 40 km southwest of Ischia when Hauptmann Schiess's wingman was forced away by two Lightnings and lost sight of his Staffelkapitän. Ten of the P-38s were shot down, but Schiess's Bf 109 G-6 "Black 1 + I" (Werknummer 160 022—factory number) crashed into the Mediterranean 30 to 50 kilometers (19 to 31 miles) south-southwest of Ischia in the Gulf of Salerno. Though not witnessed, he was probably shot down by a P-38.

On September 27 Günther von Maltzahn wrote to Schiess's parents expressing the close friendship they shared:

I ask that you and your husband accept my and my Geschwader's most sincere and heartfelt sympathy on the unspeakably hard stroke of fate which befell your son Franz.

I can sympathize with how hard it must be to come to terms with thoughts that you will never see your son Franz again in this life. One could not have wished for a better officer. Not only did there exist a comradeship and a mutual trust between Kommodore and adjutant that was tested in far more than 100 air battles, but in him I lost my best friend, on whom I could depend no matter what the situation.

He is credited with 67 aerial victories in 657 missions. Among those were 17 P-38 Lightnings, making him the highest scoring "Lightning-Killer" of the war.