Background Balance and mobility impairments are widespread in patients with Multiple Sclerosis (PwMS), even at an early stage. They can contribute to disability, physical deconditioning and reduced quality of life. Task-oriented is a training modality that may promote walking abilities and conditioning. However, the effects usually are short-lasting and exercising at home can have several barriers. This randomized controlled trial aimed to test the effectiveness of the combination of a 2-weeks in-person, supervised task-oriented circuit training (TOCT), followed by a 12-weeks home-based task-oriented program with monthly in-person visits. Methods 36 PwMS with EDSS 4–5.5 and unassisted walking have been randomly assigned to 10 supervised TOCT sessions over two weeks (Phase 1) followed by a 12-weeks home-based task-oriented program (Phase 2) or a delayed-treatment group. At the end of Phase 2, the delayed-treatment group (usual care) received the same TOCT protocol. Phase 1 was composed of six gait-based workstations and treadmill training, whereas Phase 2 was based on progressive task-oriented tasks practice at home with monthly visits to adjust activities levels. Six Minute Walk Test (6MWT), Timed 25-foot walk test (T25FW), Timed Up and Go test (TUG), Dynamic Gait Index (DGI), Modified Fatigue Impact Scale (MFIS), Multiple Sclerosis Walking Scale – 12 (MSWS-12), Multiple Sclerosis Impact Scale–29 (MSIS-29) and resting muscle oxygen consumption (rmVO2) were assessed as outcome measures at baseline, after Phase 1 and after Phase 2. Retention was tested on the whole sample at a 12-weeks follow-up. Results The entire sample completed the 2-weeks TOCT, whereas adherence was good for the 12-weeks home-based task-oriented program (6.2/10). The mean repetitions and level of difficulty of each task significantly increased after every timepoint. A superiority of task-oriented program was verified for 6MWT (F, 2,88 = 7.80; ptextless0.001) on usual care after the 12-weeks home-based program. Moreover, between-group differences were highlighted at the same point, even for T25FW, TUG and MSWS-12. RmVO2 and fatigue were significantly improved only in the experimental group. Positive effects on 6MWT were retained 12 weeks after the end of the protocol (ptextless0.001) in the whole sample. Conclusions The combination of a supervised and self-managed task-oriented program enhances walking endurance with positive effects on walking ability, fatigue and resting muscle oxygen consumption in PwMS with unassisted walking. These preliminary results reflected how this intervention was effective for impairment and activity improvements; moreover, it was cardiorespiratory stressful and possibly reduced deconditioning.