April 1944 saw the Me.410B version replace the Me.410A on the assembly lines. The main distinction of this variant was its Daimler-Benz DB 603G twelve-cylinder, liquid-cooled engine. The new engines had an increased boost and compression ratio, which allowed a takeoff power of 1,900 hp.
The aircraft's armament was reinforced. The pair of 7.92 mm Rheinmetall-Borsig MG 17 machine guns mounted in the nose section were replaced with the same number of the more powerful and efficient 13 mm large-calibre Rheinmetall-Borsig MG 131 machine guns.
Me.410B planes could now have two additional 300-litre fuel tanks suspended under their wing panels, and the main landing gear legs were extended.
Just as it was in the case of the Me.410A, two main versions of the aircraft saw full-scale production: the Me.410B-1 high-speed bomber and the Me.410B-2 "destroyer". Various Rüstsatz and Umbausatz kits were used on these aircraft.
The Me.410B-1/U2 and the Me.410B-1/U4 had armament corresponding to the same versions of the A-1 modification: either a pair of 20 mm Mauser MG 151/20 cannons (the U2 kit), or a 50 mm Rheinmetall BK 5 cannon (the U4 kit).
The Me.410B-2/U2 version of the aircraft had a WB 151 ventral container with two more 20 mm Mauser MG 151/20 cannons.
In addition to the 50 mm Rheinmetall BK 5 cannon mounted in the bomb bay, Me.410B-2/U4 planes had a pair of 30 mm Rheinmetall-Borsig MK 103 cannons installed. To make room, their 20 mm Mauser MG 151/20 cannon and 13 mm Rheinmetall-Borsig MG 131 machine guns were removed. About a hundred such kits were delivered to the Luftwaffe's troops on the front lines.
Several more "field modification kits" for the Me.410B-2 were developed for the purpose of fighting Allied bombers. The R2 kit included a WB 108 container with two 30 mm Rheinmetall-Borsig MK 108 cannons. The R3 kit also allowed the mounting of additional 30 mm cannons of a different type (Rheinmetall-Borsig MK 103) in a WB 103 container.
In addition to a WB 151 container, planes equipped with the R4 kit received two additional 20 mm Mauser MG 151/20 cannons mounted under the fuselage. Planes with the R5 kit received a container with four Mauser MG 151/20 cannons, mounted in the bomb bay.
In April 1944, several Me.410B-2/U4 aircraft received a 37 mm Rheinmetall BK 3,7 aircraft anti-tank cannon for trial.