The efficacy of herbicides combinations in managing annual weed flora and to assess their effect on soil microbes in sugarcane (Saccharum officinarum L.) were evaluated during 2018-19 and 2019-20 cropping seasons at the Kenya Agricultural and Livestock Research Organization in Kisumu, Kenya. The sugarcane (variety KEN 83-737) field with natural weed infestation  was used for experimentation in a randomized complete block design (RCBD) with four replications. The tested treatments included: post-emergence applications (PoE) of metribuzin 960g/ha; diuron + hexazinone + sulfometuron-methyl 603 + 170 + 14.5 g/ha; trifloxysulfuron-sodium + ametryn 1097 + 27.8 g/ha; diuron + hexazinone 1170 + 330 g/ha; untreated/weedy check, and hand hoeing twice at 30 and 45 days after sugarcane planting (DAP). The weed density, sugarcane tiller numbers, cane height, millable stalks, and cane yield were significantly different (p< 0.05) across the treatments. All herbicides and the hand hoeing twice proved effective for weed control, resulting in higher sugarcane yields. The combination of diuron, hexazinone, and sulfometuron-methyl resulted in the best weed control, albeit with slight phytotoxicity. The herbicides exhibited varying levels of efficacy in weed control, phytotoxic effects on sugarcane, and impacts on microbial composition and cane yield. Diuron + hexazinone 1170 + 330 g/ha PoE recorded the highest net returns amongst the tested treatments.