Barley-based cropping systems (BCS) alter barley production by influencing weed infestation rates and soil nutrient dynamics. This two-year field study evaluated the interactive effects of five BCS and five weed control strategies (WCS) on soil properties and the growth and yield of barley. Barley was planted in five different cropping systems, i.e., fallow-barley (FB), maize-barley (MaB), cotton-barley (CB), mungbean-barley (MuB) and sorghum-barley (SB). Similarly, five different WCS, weed-free (control, WF), weedy-check (control, WC), false seedbeds (FS), chemical control (CC) and use of allelopathic water extracts (AWE), were included in the study. The SB system had the highest soil bulk density (1.48 and 1.47 g cm−3 during the period 2017–2018 and 2018–2019, respectively) and lowest total soil porosity (41.40 and 41.07% during the period 2017–2018 and 2018–2019, respectively). However, WCS remained non-significant for bulk density and total soil porosity during both years of the study. Barley with WF had a higher leaf area index (5.28 and 4.75) and specific leaf area (65.5 and 64.9 cm−2 g−1) compared with barley grown under WC. The MuB system under WC had the highest values of extractable NH4-N (5.42 and 5.58 mg kg−1), NO3-N (5.79 and 5.93 mg kg−1), P (19.9 and 19.5 mg kg−1), and K (195.6 and 194.3 mg kg−1) with statistically similar NO3-N in the MaB system under WC and extractable K in the MuB system under FS. Grain yield ranged between 2.8–3.2 and 2.9–3.3 t ha−1 during the period 2017–2018 and 2018–2019, respectively, among different WCS. Similarly, grain yield ranged between 2.9–3.2 and 3.0–3.2 t ha−1 during the period 2017–2018 and 2018–2019, respectively, within different BCS. Among WCS, the highest grain yield (3.29 and 3.32 t ha−1) along with yield-related traits of barley were in WF as compared to WC. Overall, MuB system recorded better yield and yield-related traits, whereas the lowest values of these traits were recorded for FB systems. In conclusion, the MuB system with WF improved soil characteristics and barley yield over other cropping systems. The AWE significantly suppressed weeds and was equally effective as the chemical control. Therefore, MuB and AWE could be used to improve barley productivity and suppress weeds infestation.