The use of non- and low-caloric sweetener(s) (NCS and LCS) as a means to prevent overweight and obesity is highly debated, as both NCS and LCS have been proposed to have a negative impact on energy homeostasis. This systematic review aimed to assess the impact of NCS and LCS on fasting and postprandial substrate oxidation, energy expenditure, and catecholamines, compared to caloric sweeteners or water, across different doses and types of NCS and LCS, acutely and in the longer-term. A total of 20 studies were eligible: 16 studies for substrate oxidation and energy expenditure and four studies for catecholamines. Most studies compared the acute effects of NCS or LCS with caloric sweeteners under non-isoenergetic conditions. These studies generally found higher fat oxidation and lower carbohydrate oxidation with NCS or LCS than with caloric sweeteners. Findings for energy expenditure were inconsistent. With the limited number of studies, no convincing pattern for the remaining outcomes and comparisons could be seen. In conclusion, drinks or meals with NCS or LCS resulted in higher fat and lower carbohydrate oxidation compared to caloric sweeteners. No other conclusions could be drawn due to insufficient or inconsistent results. Further studies in this research field are warranted.